Ubiquitin
Encyclopedia
Ubiquitin is a small regulatory protein
that has been found in almost all tissues (ubiquitously) of eukaryotic organisms. Among other functions, it directs protein recycling.
Ubiquitin can be attached to proteins and label them for destruction. The ubiquitin tag directs proteins to the proteasome
, which is a large protein complex
in the cell that degrades and recycles unneeded proteins. This discovery won the Nobel Prize
for chemistry in 2004.
Ubiquitin tags can also direct proteins to other locations in the cell, where they control other protein and cell mechanisms.
protein of unknown function expressed in all eukaryotic
cells. The basic functions of ubiquitin and the components of the ubiquitination pathway were elucidated in the early 1980s in groundbreaking work performed at Fox Chase Cancer Center
by Aaron Ciechanover
, Avram Hershko
, and Irwin Rose
for which the Nobel Prize in Chemistry
was awarded in 2004.
The ubiquitylation system was initially characterised as an ATP
-dependent proteolytic system present in cellular extracts. A heat-stable polypeptide
present in these extracts, ATP-dependent proteolysis factor 1 (APF-1), was found to become covalently attached to the model protein substrate lysozyme
in an ATP
- and Mg
2+-dependent process. Multiple APF-1 molecules were linked to a single substrate
molecule by an isopeptide linkage, and conjugates were found to be rapidly degraded with the release of free APF-1. Soon after APF-1-protein conjugation was characterised, APF-1 was identified as ubiquitin. The carboxyl group of the C-terminal glycine residue of ubiquitin (Gly76) was identified as the moiety conjugated to substrate lysine
residues.
Ubiquitin is a small protein
that exists in all eukaryotic
cell
s. It performs its myriad functions through conjugation to a large range of target proteins. A variety of different modifications can occur. The ubiquitin protein itself consists of 76 amino acid
s and has a molecular mass
of about 8.5 kDa. Key features include its C-terminal tail and the 7 lysine
residues. It is highly conserved among eukaryotic species: Human and yeast ubiquitin share 96% sequence identity. The human ubiquitin sequence in one-letter code (lysine residues in bold):
genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. The UBB
and UBC
genes code for polyubiquitin precursor proteins.
biosynthesis, interacts with MoeB, which acts like an E1 ubiquitin-activating enzyme
for MoaD, strengthening the link between these prokaryotic proteins and the ubiquitin system. A similar system exists for ThiS, with its E1-like enzyme ThiF. It is also believed that the Saccharomyces cerevisiae
protein Urm-1, a ubiquitin-related modifier, is a "molecular fossil" that connects the evolutionary relation with the prokaryotic ubiquitin-like molecules and ubiquitin.
The process of marking a protein with ubiquitin (ubiquitylation or ubiquitination) consists of a series of steps:
In the ubiquitination cascade, E1 can bind with dozens of E2s, which can bind with hundreds of E3s in a hierarchical way. Other ubiquitin-like proteins (ULPs) are also modified via the E1–E2–E3 cascade.
:
Transfer can occur in two ways:
The anaphase-promoting complex
(APC) and the SCF complex
(for Skp1-Cullin-F-box protein complex) are two examples of multi-subunit
E3s involved in recognition and ubiquitination of specific target proteins for degradation by the proteasome
.
residues in a process termed multiubiquitination. As discussed, ubiquitin possesses a total of 7 lysine residues. Historically the original type of ubiquitin chains identified were those linked via lysine 48. However, more recent work has uncovered a wide variety of linkages involving all possible lysine residues and in addition chains assembled on the N-terminus of a ubiquitin molecule ("linear chains"). Work published in 2007 has demonstrated the formation of branched ubiquitin chains containing multiple linkage types. "Atypical" (non-lysine 48-linked) ubiquitin chains have been discussed in a review by Ikeda & Dikic.
The ubiquitination system functions in a wide variety of cellular processes, including:
. At least four ubiquitin molecules must be attached to lysine residues on the condemned protein in order for it to be recognised by the 26S. Lysine 63 linked chains direct the localization of proteins. Monoubiquitylation of proteins also targets the localization of proteins -proteasome
. The proteasome
is a complex, barrel-shaped structure with two chambers, within which proteolysis occurs. Proteins are rapidly degraded into small peptide
s (usually 3-24 amino acid
residues in length). Ubiquitin molecules are cleaved off the protein immediately prior to destruction and are recycled for further use. Although the majority of proteasomal substrates are ubiquitinated, there are examples of non-ubiquitinated proteins targeted to the proteasome.
s (for example, receptors
) for removal from membranes
and fulfill several signaling roles within the cell. Cell-surface transmembrane molecules that are tagged with ubiquitin are often monoubiquitinated, and this modification alters the subcellular localization of the protein, often targeting the protein for destruction in lysosomes.
Histones are usually monoubiquitinated and associated with signaling or structural marking.
residues that may serve as points of polyubiquitylation, they are; K48, K63, K6, K11, K27, K29 and K33. These different linkages may define unique signals that are recognized by ubiquitin-binding proteins, which have Ubiquitin interacting motifs (UIMs) that bind to ubiquitin. It is thought that the different linkages are recognized by proteins that are specific for the unique topologies
that are intrinsic to the linkage. One example, is the K63 linkage, which is known to be involved in DNA damage recognition
of DNA double-strand breaks. The K63 linkage appears to be placed on the H2AX histone
by the E2/E3 ligase pair
, Ubc13-Mms2/RNF168. This K63 chain appears to recruit RAP80, which contains a UIM, and RAP80
then helps localize BRCA1
. This pathway will eventually recruit the necessary proteins for Homologous Recombination Repair.
gene may be erroneously transcribed due to a monotonic nucleotide sequence in the coding region of the gene. As a result, a dinucleotide deletion occurs at the mRNA level causing a frameshift. When translated into protein, a dysfunctional ubiquitin that has lost its C-terminal glycine
and has a peptide of 20 amino acids instead is generated. UBB+1
has shown to accumulate selectively in tauopathies
and polyglutaminopathies.
to ubiquitin are used in histology
to identify abnormal accumulations of protein inside cells that are markers of disease. These accumulations are called inclusion bodies. Examples of such abnormal inclusions in cells are
), ubiquitin cross-reactive protein (UCRP, also known as interferon-stimulated gene-15 ISG15
), ubiquitin-related modifier-1 (URM1), neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8
, also called Rub1 in S. cerevisiae
), human leukocyte antigen F-associated (FAT10), autophagy-8 (ATG8
) and -12 (ATG12
), Fau ubiquitin-like protein (FUB1
), MUB (membrane-anchored UBL), ubiquitin fold-modifier-1 (UFM1
) and ubiquitin-like protein-5 (UBL5
, which is but known as homologous to ubiquitin-1 [Hub1] in S. pombe
). Whilst these proteins share only modest primary sequence identity with ubiquitin, they are closely related three-dimensionally. For example, SUMO shares only 18% sequence identity, but contain the same structural fold. This fold is called "ubiquitin fold" or sometimes called ubiquiton fold. FAT10 and UCRP contain two. This compact globular beta-grasp fold is found in ubiquitin, UBLs, and proteins that comprise a ubiquitin-like domain e.g. the S. cerevisiae spindle pole body duplication protein, Dsk2, and NER protein, Rad23, both contain N-terminal ubiquitin domains.
These related molecules have novel functions and influence diverse biological processes. There is also cross-regulation between the various conjugation pathways since some proteins can become modified by more than one UBL, and sometimes even at the same lysine residue. For instance, SUMO modification often acts antagonistically to that of ubiquitination and serves to stabilize protein substrates. Proteins conjugated to UBLs are typically not targeted for degradation by the proteasome, but rather function in diverse regulatory activities. Attachment of UBLs might alter substrate conformation, affect the affinity for ligands or other interacting molecules, alter substrate localization and influence protein stability.
UBLs are structurally similar to ubiquitin and are processed, activated, conjugated and released from conjugates by enzymatic steps that are similar to the corresponding mechanisms for ubiquitin. UBLs are also translated with C-terminal extensions that are processed to expose the invariant C-terminal LRGG. These modifiers have their own specific E1 (activating), E2 (conjugating) and E3 (ligating) enzymes that conjugate the UBLs to intracellular targets. These conjugates can be reversed by UBL-specific isopeptidases that have similar mechanisms to that of the deubiquitinating enzymes.
Within some species, the recognition and destruction of sperm mitochondria through a mechanism involving ubiquitin is responsible for sperm mitochondria's disposal after fertilization occurs.
; BAT3; DDI1; DDI2; FAU
; HERPUD1
; HERPUD2;
HOPS
; IKBKB; ISG15
; LOC391257; MIDN; NEDD8
; OASL
; PARK2;
RAD23A
; RAD23B
; RPS27A
; SACS
; SF3A1
; SUMO1; SUMO2
; SUMO3
;
SUMO4
; TMUB1; TMUB2
; UBA52
; UBB
; UBC
; UBD; UBFD1;
UBL4; UBL4A
; UBL4B; UBL7; UBLCP1; UBQLN1
; UBQLN2
; UBQLN3;
UBQLN4; UBQLNL; UBTD1; UBTD2; UHRF1
; UHRF2
;
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that has been found in almost all tissues (ubiquitously) of eukaryotic organisms. Among other functions, it directs protein recycling.
Ubiquitin can be attached to proteins and label them for destruction. The ubiquitin tag directs proteins to the proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
, which is a large protein complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
in the cell that degrades and recycles unneeded proteins. This discovery won the Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...
for chemistry in 2004.
Ubiquitin tags can also direct proteins to other locations in the cell, where they control other protein and cell mechanisms.
Identification
Ubiquitin (originally, ubiquitous immunopoietic polypeptide) was first identified in 1975 as an 8.5-kDaAtomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
protein of unknown function expressed in all eukaryotic
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
cells. The basic functions of ubiquitin and the components of the ubiquitination pathway were elucidated in the early 1980s in groundbreaking work performed at Fox Chase Cancer Center
Fox Chase Cancer Center
The Fox Chase Cancer Center is a National Cancer Institute-designated Comprehensive Cancer Center research facility and hospital located in the Fox Chase section of Philadelphia, Pennsylvania, United States. The main facilities of the center are located on property adjoining Burholme Park...
by Aaron Ciechanover
Aaron Ciechanover
Aaron Ciechanover is an Israeli biologist, and Nobel laureate in Chemistry.- Biography :Ciechanover was born in Haifa, British mandate of Palestine, a year before the establishment of the State of Israel...
, Avram Hershko
Avram Hershko
Avram Hershko is a Hungarian-Israeli biochemist and Nobel laureate in Chemistry.-Biography:Born Herskó Ferenc in Karcag, Hungary, Hershko emigrated to Israel in 1950. Received his M.D. in 1965 and his Ph.D in 1969 from the Hebrew University-Hadassah Medical School, Jerusalem, Israel...
, and Irwin Rose
Irwin Rose
Irwin A. Rose is an American biologist. Along with Aaron Ciechanover and Avram Hershko, he was awarded the 2004 Nobel Prize in Chemistry for the discovery of ubiquitin-mediated protein degradation.-Biography:...
for which the Nobel Prize in Chemistry
Nobel Prize in Chemistry
The Nobel Prize in Chemistry is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in chemistry, physics, literature,...
was awarded in 2004.
The ubiquitylation system was initially characterised as an ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
-dependent proteolytic system present in cellular extracts. A heat-stable polypeptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
present in these extracts, ATP-dependent proteolysis factor 1 (APF-1), was found to become covalently attached to the model protein substrate lysozyme
Lysozyme
Lysozyme, also known as muramidase or N-acetylmuramide glycanhydrolase, are glycoside hydrolases, enzymes that damage bacterial cell walls by catalyzing hydrolysis of 1,4-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in a peptidoglycan and between...
in an ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
- and Mg
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
2+-dependent process. Multiple APF-1 molecules were linked to a single substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
molecule by an isopeptide linkage, and conjugates were found to be rapidly degraded with the release of free APF-1. Soon after APF-1-protein conjugation was characterised, APF-1 was identified as ubiquitin. The carboxyl group of the C-terminal glycine residue of ubiquitin (Gly76) was identified as the moiety conjugated to substrate lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
residues.
The protein
| Number of residues | 76 |
| Molecular mass Molecular mass The molecular mass of a substance is the mass of one molecule of that substance, in unified atomic mass unit u... |
8564.47 Da |
| Isoelectric point Isoelectric point The isoelectric point , sometimes abbreviated to IEP, is the pH at which a particular molecule or surface carries no net electrical charge.... (pI) |
6.79 |
| Gene names | RPS27A RPS27A 40S ribosomal protein S27a is a protein that in humans is encoded by the RPS27A gene.-Further reading:... (UBA80, UBCEP1), UBA52 UBA52 60S ribosomal protein L40 is a protein that in humans is encoded by the UBA52 gene.-Further reading:... (UBCEP2), UBB Ubiquitin B Ubiquitin is a protein that in humans is encoded by the UBB gene.- Function :Ubiquitin, one of the most conserved proteins known. Ubiquitin is required for ATP-dependent, non-lysosomal intracellular protein degradation of abnormal proteins and normal proteins with a rapid turnover... , UBC Ubiquitin C Ubiquitin is a protein that in humans is encoded by the UBC gene.-Interactions:Ubiquitin C has been shown to interact with SCNN1A, SCNN1G, Parkin , P70-S6 Kinase 1, TRAF6, HDAC3, SFPQ, S100A10, Mothers against decapentaplegic homolog 3, NOTCH1, HIF1A, Epidermal growth factor receptor, E2F1,... |
Ubiquitin is a small protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that exists in all eukaryotic
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s. It performs its myriad functions through conjugation to a large range of target proteins. A variety of different modifications can occur. The ubiquitin protein itself consists of 76 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s and has a molecular mass
Molecular mass
The molecular mass of a substance is the mass of one molecule of that substance, in unified atomic mass unit u...
of about 8.5 kDa. Key features include its C-terminal tail and the 7 lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
residues. It is highly conserved among eukaryotic species: Human and yeast ubiquitin share 96% sequence identity. The human ubiquitin sequence in one-letter code (lysine residues in bold):
| MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG |
Genes
Ubiquitin is encoded in mammals by 4 different genes. UBA52 and RPS27ARPS27A
40S ribosomal protein S27a is a protein that in humans is encoded by the RPS27A gene.-Further reading:...
genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. The UBB
Ubiquitin B
Ubiquitin is a protein that in humans is encoded by the UBB gene.- Function :Ubiquitin, one of the most conserved proteins known. Ubiquitin is required for ATP-dependent, non-lysosomal intracellular protein degradation of abnormal proteins and normal proteins with a rapid turnover...
and UBC
Ubiquitin C
Ubiquitin is a protein that in humans is encoded by the UBC gene.-Interactions:Ubiquitin C has been shown to interact with SCNN1A, SCNN1G, Parkin , P70-S6 Kinase 1, TRAF6, HDAC3, SFPQ, S100A10, Mothers against decapentaplegic homolog 3, NOTCH1, HIF1A, Epidermal growth factor receptor, E2F1,...
genes code for polyubiquitin precursor proteins.
Origins
No ubiquitin and ubiquitination machinery are known to exist in prokaryotes. However, ubiquitin is believed to have descended from prokaryotic proteins similar to ThiS or MoaD. These prokaryotic proteins, despite having little sequence identity (ThiS has 14% identity to ubiquitin), share the same protein fold. These proteins also share sulfur chemistry with ubiquitin. MoaD, which is involved in molybdenum cofactorMolybdenum cofactor
Molybdenum cofactor is a cofactor required for the activity of enzymes such as sulfite oxidase, xanthine oxidoreductase, and aldehyde oxidase. It is a coordination complex formed between molybdopterin and an oxide of molybdenum.Molybdopterins, in turn, are synthesized from guanosine triphosphate...
biosynthesis, interacts with MoeB, which acts like an E1 ubiquitin-activating enzyme
Ubiquitin-activating enzyme
Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which targets a protein for degradation via a proteasome. This covalent attachment of ubiquitin or ubiquitin-like proteins to targeted proteins is a major mechanism for regulating protein...
for MoaD, strengthening the link between these prokaryotic proteins and the ubiquitin system. A similar system exists for ThiS, with its E1-like enzyme ThiF. It is also believed that the Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
protein Urm-1, a ubiquitin-related modifier, is a "molecular fossil" that connects the evolutionary relation with the prokaryotic ubiquitin-like molecules and ubiquitin.
Ubiquitination (ubiquitylation)
Ubiquitination is an enzymatic, protein post-translational modification (PTM) process in which the carboxylic acid of the terminal glycine from the di-glycine motif in the activated ubiquitin forms an amide bond to the epsilon amine of the lysine in the modified protein.The process of marking a protein with ubiquitin (ubiquitylation or ubiquitination) consists of a series of steps:
- Activation of ubiquitin: Ubiquitin is activated in a two-step reaction by an E1 ubiquitin-activating enzyme in a process requiring ATPAdenosine triphosphateAdenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
as an energy source. The initial step involves production of a ubiquitin-adenylate intermediate. The second step transfers ubiquitin to the E1 active siteActive siteIn biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
cysteineCysteineCysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residue, with release of AMPAdenosine monophosphateAdenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
. This step results in a thioester linkage between the C-terminal carboxyl group of ubiquitin and the E1 cysteine sulfhydryl groupThiolIn organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
. - Transfer of ubiquitin from E1 to the active siteActive siteIn biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
cysteine of a ubiquitin-conjugating enzymeUbiquitin-conjugating enzymeUbiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome.The ubiquitination process covalently attaches ubiquitin, a short protein of 76...
E2 via a trans(thio)esterification reaction. Mammalian genomes contain 30-40 UBCs. - The final step of the ubiquitylation cascade creates an isopeptide bond between a lysine of the target protein and the C-terminal glycine of ubiquitin. In general, this step requires the activity of one of the hundreds of E3 ubiquitin-protein ligases (often termed simply ubiquitin ligaseUbiquitin ligaseA ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
). E3 enzymes function as the substrateSubstrate (biochemistry)In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
recognition modules of the system and are capable of interaction with both E2 and substrateSubstrate (biochemistry)In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
.
In the ubiquitination cascade, E1 can bind with dozens of E2s, which can bind with hundreds of E3s in a hierarchical way. Other ubiquitin-like proteins (ULPs) are also modified via the E1–E2–E3 cascade.
E3
E3 enzymes possess one of two domainsProtein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
:
- The HECTHECT domainIn molecular biology, the HECT domain is a protein domain found in ubiquitin-protein ligases. The name HECT comes from Homologous to the E6-AP Carboxyl Terminus'. Proteins containing this domain at the C terminus include ubiquitin-protein ligase, which regulates ubiquitination of...
(Homologous to the E6-AP Carboxyl Terminus) domain - The RINGRING finger domainIn molecular biology, a RING finger domain is a protein structural domain of zinc finger type which contains a Cys3HisCys4 amino acid motif which binds two zinc cations. This protein domain contains from 40 to 60 amino acids...
(Really Interesting New Gene) domain (or the closely related U-box domain)
Transfer can occur in two ways:
- Directly from E2, catalysed by RING domain E3s.
- Via an E3 enzyme, catalysed by HECT domain E3s. In this case, a covalent E3-ubiquitin intermediate is formed before transfer of ubiquitin to the substrate protein.
The anaphase-promoting complex
Anaphase-promoting complex
Anaphase-Promoting Complex, also called cyclosome , is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin and RING subunit much like SCF...
(APC) and the SCF complex
SCF complex
Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation...
(for Skp1-Cullin-F-box protein complex) are two examples of multi-subunit
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
E3s involved in recognition and ubiquitination of specific target proteins for degradation by the proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
.
Function and variety of ubiquitin modifications
Following addition of a single ubiquitin moiety to a protein substrate (monoubiquitination), further ubiquitin molecules can be added to the first, yielding a polyubiquitin chain. In addition, some substrates are modified by addition of ubiquitin molecules to multiple lysineLysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
residues in a process termed multiubiquitination. As discussed, ubiquitin possesses a total of 7 lysine residues. Historically the original type of ubiquitin chains identified were those linked via lysine 48. However, more recent work has uncovered a wide variety of linkages involving all possible lysine residues and in addition chains assembled on the N-terminus of a ubiquitin molecule ("linear chains"). Work published in 2007 has demonstrated the formation of branched ubiquitin chains containing multiple linkage types. "Atypical" (non-lysine 48-linked) ubiquitin chains have been discussed in a review by Ikeda & Dikic.
The ubiquitination system functions in a wide variety of cellular processes, including:
- Antigen processingAntigen processingAntigen processing is a biological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. This process involves two distinct pathways for processing of antigens from an organism's own proteins or intracellular pathogens , or from phagocytosed...
- ApoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
- BiogenesisBiogenesisBiogenesis is the law that living things come only from other living things, e.g. a spider lays eggs, which develop into spiders. It may also refer to biochemical processes of production in living organisms.-Spontaneous generation:...
of organelles - Cell cycle and division
- DNA transcriptionTranscription (genetics)Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
and repair - Differentiation and development
- Immune response and inflammation
- Neural and muscular degeneration
- Morphogenesis of neural networks
- Modulation of cell surface receptors, ion channels and the secretory pathway
- Response to stress and extracellular modulators
- Ribosome biogenesis
- Viral infection
Lysine linked chains
The most studied polyubiquitin chains - lysine48-linked - target proteins for destruction, a process known as proteolysisProteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
. At least four ubiquitin molecules must be attached to lysine residues on the condemned protein in order for it to be recognised by the 26S. Lysine 63 linked chains direct the localization of proteins. Monoubiquitylation of proteins also targets the localization of proteins -proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
. The proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
is a complex, barrel-shaped structure with two chambers, within which proteolysis occurs. Proteins are rapidly degraded into small peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s (usually 3-24 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues in length). Ubiquitin molecules are cleaved off the protein immediately prior to destruction and are recycled for further use. Although the majority of proteasomal substrates are ubiquitinated, there are examples of non-ubiquitinated proteins targeted to the proteasome.
Monoubiquitination
Ubiquitin can also mark transmembrane proteinTransmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
s (for example, receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
) for removal from membranes
Biological membrane
A biological membrane or biomembrane is an enclosing or separatingmembrane that acts as a selective barrier, within or around a cell. It consists of a lipid bilayer with embedded proteins that may constitute close to 50% of membrane content...
and fulfill several signaling roles within the cell. Cell-surface transmembrane molecules that are tagged with ubiquitin are often monoubiquitinated, and this modification alters the subcellular localization of the protein, often targeting the protein for destruction in lysosomes.
Histones are usually monoubiquitinated and associated with signaling or structural marking.
Other chain types
Ubiquitin has seven lysineLysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
residues that may serve as points of polyubiquitylation, they are; K48, K63, K6, K11, K27, K29 and K33. These different linkages may define unique signals that are recognized by ubiquitin-binding proteins, which have Ubiquitin interacting motifs (UIMs) that bind to ubiquitin. It is thought that the different linkages are recognized by proteins that are specific for the unique topologies
Topology
Topology is a major area of mathematics concerned with properties that are preserved under continuous deformations of objects, such as deformations that involve stretching, but no tearing or gluing...
that are intrinsic to the linkage. One example, is the K63 linkage, which is known to be involved in DNA damage recognition
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
of DNA double-strand breaks. The K63 linkage appears to be placed on the H2AX histone
H2AFX
H2AX is one of several genes coding for histone H2A. In humans and other eukaryotes, the DNA is wrapped around histone-groups, consisting of core histones H2A, H2B, H3 and H4. Thus, the H2AX contributes to the histone-formation and therefore the structure of DNA.H2AX becomes phosphorylated on...
by the E2/E3 ligase pair
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
, Ubc13-Mms2/RNF168. This K63 chain appears to recruit RAP80, which contains a UIM, and RAP80
UIMC1
BRCA1-A complex subunit RAP80 is a protein that in humans is encoded by the UIMC1 gene.-Further reading:...
then helps localize BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
. This pathway will eventually recruit the necessary proteins for Homologous Recombination Repair.
Genetic disorders
Some genetic disorders associated with ubiquitin are:- The gene that controls "ubiquitin-1", which is found in lesions associated with Alzheimer's and Parkinson's disease. Two transcript variants encoding different isoforms have been found for this gene.Higher levels of ubiquitin in the brain decreased malformation of the APP molecule, which plays a key role in triggering Alzheimer's disease. Conversly, lower levels of ubiquilin-1 in the brain were associated with increased malformation of APP.
- The gene whose disruption causes Angelman syndromeAngelman syndromeAngelman syndrome is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements , frequent laughter or smiling, and usually a happy demeanor....
, UBE3AUBE3AUbiquitin-protein ligase E3A also known as E6AP ubiquitin-protein ligase is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells...
, encodes a ubiquitin ligase (E3) enzyme termed E6-AP. - The gene disrupted in Von Hippel-Lindau syndrome encodes a ubiquitin E3 ligase termed the VHL tumor suppressor or VHL gene.
- The gene disrupted in Liddle's SyndromeLiddle's SyndromeLiddle's syndrome, also called Liddle syndrome and pseudoaldosteronism, is an autosomal dominant disorder characterized by early, and frequently severe, hypertension associated with low plasma renin activity, metabolic alkalosis due to hypokalemia, and hypoaldosteronism...
results in disregulation of an epithelial Na+ channel (ENaCEpithelial sodium channelThe epithelial sodium channel is a membrane-bound ion-channel that is permeable for Li+-ions, protons and especially Na+-ions. It is a constitutively active ion-channel...
) and causes hypertensionHypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
. - Eight of the thirteen identified genes whose disruption causes Fanconi anemiaFanconi anemiaFanconi anemia is a genetic disease with an incidence of 1 per 350,000 births, with a higher frequency in Ashkenazi Jews and Afrikaners in South Africa.FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair...
encode proteins that form a large ubiquitin ligase (E3) complex. - Mutations of the Cullin7CUL7Cullin-7 is a protein that in humans is encoded by the CUL7 gene.-External Links:* *...
E3 ubiquitin ligase are linked to 3-M syndrome3-M syndrome3-M syndrome , is a rare hereditary growth retardation syndrome. The name 3-M originates from the initials of the three authors Miller, McKusick and Malvaux who first reported the syndrome in literature...
, an autosomal-recessive growth retardation disorder
Frameshift mutant (UBB+1)
The ubiquitin BUbiquitin B
Ubiquitin is a protein that in humans is encoded by the UBB gene.- Function :Ubiquitin, one of the most conserved proteins known. Ubiquitin is required for ATP-dependent, non-lysosomal intracellular protein degradation of abnormal proteins and normal proteins with a rapid turnover...
gene may be erroneously transcribed due to a monotonic nucleotide sequence in the coding region of the gene. As a result, a dinucleotide deletion occurs at the mRNA level causing a frameshift. When translated into protein, a dysfunctional ubiquitin that has lost its C-terminal glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
and has a peptide of 20 amino acids instead is generated. UBB+1
UBB+1
UBB+1 is shorthand for Ubiquitin-B+1, a frameshifted mutant arising from the Ubiquitin B gene. UBB+1 is thought to arise from molecular misreading, a poorly understood process. Molecular misreading introduces dinucleotide deletions into mRNA transcripts. These deletions are not present in...
has shown to accumulate selectively in tauopathies
Tauopathy
Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in the human brain.The best known of these illnesses is Alzheimer's disease , where tau protein is deposited within neurons in the form of neurofibrillary tangles...
and polyglutaminopathies.
Immunohistochemistry
AntibodiesAntibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
to ubiquitin are used in histology
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
to identify abnormal accumulations of protein inside cells that are markers of disease. These accumulations are called inclusion bodies. Examples of such abnormal inclusions in cells are
- Neurofibrillary tangleNeurofibrillary tangleNeurofibrillary Tangles are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary marker of Alzheimer's Disease. Their presence is also found in numerous other diseases known as Tauopathies...
s in Alzheimer's diseaseAlzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death... - Lewy bodyLewy bodyLewy bodies are abnormal aggregates of protein that develop inside nerve cells in Parkinson's disease , Lewy Body Dementia and some other disorders. They are identified under the microscope when histology is performed on the brain....
in Parkinson's diseaseParkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system... - Pick bodies in Pick's diseasePick's diseasePick's disease, is a rare neurodegenerative disease that causes progressive destruction of nerve cells in the brain. Symptoms include loss of speech , and dementia. While some of the symptoms can initially be alleviated, the disease progresses and patients often die within two to ten years...
- Inclusions in motor neuron disease and Huntington's DiseaseHuntington's diseaseHuntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
- Mallory bodiesMallory bodyIn histopathology, a Mallory body, Mallory-Denk body, and Mallory's hyaline, is an inclusion found in the cytoplasm of liver cells.-Associated conditions:...
in alcoholic liver diseaseAlcoholic liver diseaseAlcoholic liver disease is a term that encompasses the hepatic manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and chronic hepatitis with hepatic fibrosis or cirrhosis. It is the major cause of liver disease in Western countries... - Rosenthal fiberRosenthal fiberA Rosenthal fiber is a thick, elongated, worm-like or "corkscrew" eosinophilic bundle that is found on H&E staining of the brain in the presence of long standing gliosis, occasional tumors, and some metabolic disorders.-Associated conditions:...
s in astrocyteAstrocyteAstrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s
Ubiquitin-like modifiers
Although ubiquitin is the most well understood post-translation modifier, there is a growing family of ubiquitin-like proteins (UBLs) that modify cellular targets in a pathway that is parallel to, but distinct from, that of ubiquitin. Known UBLs include: small ubiquitin-like modifier (SUMOSUMO protein
Small Ubiquitin-like Modifier or SUMO proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function...
), ubiquitin cross-reactive protein (UCRP, also known as interferon-stimulated gene-15 ISG15
ISG15
Interferon-induced 17 kDa protein is a protein that in humans is encoded by the ISG15 gene. ISG15 shares several common properties with other ubiquitin-like molecules , but its activity is tightly regulated by specific signaling pathways that have a role in innate immunity...
), ubiquitin-related modifier-1 (URM1), neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8
NEDD8
NEDD8 is a protein that in humans is encoded by the NEDD8 gene. This ubiquitin-like protein , which becomes covalently conjugated to a limited number of cellular proteins in a manner analogous to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin...
, also called Rub1 in S. cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
), human leukocyte antigen F-associated (FAT10), autophagy-8 (ATG8
ATG8
Autophagy-related protein 8 is a ubiquitin-like protein required for the formation of autophagosomal membranes. The transient conjugation of Atg8 to the autophagosomal membrane through a ubiquitin-like conjugation system is essential for autophagy in eukaryotes...
) and -12 (ATG12
ATG12
Autophagy-related protein 12 is a protein that in humans is encoded by the ATG12 gene.-Further reading:...
), Fau ubiquitin-like protein (FUB1
FAU (gene)
40S ribosomal protein S30 is a protein that in humans is encoded by the FAU gene.-Further reading:...
), MUB (membrane-anchored UBL), ubiquitin fold-modifier-1 (UFM1
UFM1
Ubiquitin-fold modifier 1, also known as UFM1, is a protein which in humans is encoded by the UFM1 gene.UFM1 is a ubiquitin-like protein that is conjugated to target proteins by E1-like activating enzyme UBA5 and E2-like conjugating enzyme UFC1 .- Function :UFM1 shares several common properties...
) and ubiquitin-like protein-5 (UBL5
UBL5
Ubiquitin-like protein 5 is a protein that in humans is encoded by the UBL5 gene.It has been shown that its expression levels is higher in C. elegans mitochondria treated to lower expression of certain electron transport chain proteins during the L3/L4 stage. These worms have increased lifespans....
, which is but known as homologous to ubiquitin-1 [Hub1] in S. pombe
Schizosaccharomyces pombe
Schizosaccharomyces pombe, also called "fission yeast", is a species of yeast. It is used as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measure 3 to 4 micrometres in diameter and 7 to 14 micrometres in length...
). Whilst these proteins share only modest primary sequence identity with ubiquitin, they are closely related three-dimensionally. For example, SUMO shares only 18% sequence identity, but contain the same structural fold. This fold is called "ubiquitin fold" or sometimes called ubiquiton fold. FAT10 and UCRP contain two. This compact globular beta-grasp fold is found in ubiquitin, UBLs, and proteins that comprise a ubiquitin-like domain e.g. the S. cerevisiae spindle pole body duplication protein, Dsk2, and NER protein, Rad23, both contain N-terminal ubiquitin domains.
These related molecules have novel functions and influence diverse biological processes. There is also cross-regulation between the various conjugation pathways since some proteins can become modified by more than one UBL, and sometimes even at the same lysine residue. For instance, SUMO modification often acts antagonistically to that of ubiquitination and serves to stabilize protein substrates. Proteins conjugated to UBLs are typically not targeted for degradation by the proteasome, but rather function in diverse regulatory activities. Attachment of UBLs might alter substrate conformation, affect the affinity for ligands or other interacting molecules, alter substrate localization and influence protein stability.
UBLs are structurally similar to ubiquitin and are processed, activated, conjugated and released from conjugates by enzymatic steps that are similar to the corresponding mechanisms for ubiquitin. UBLs are also translated with C-terminal extensions that are processed to expose the invariant C-terminal LRGG. These modifiers have their own specific E1 (activating), E2 (conjugating) and E3 (ligating) enzymes that conjugate the UBLs to intracellular targets. These conjugates can be reversed by UBL-specific isopeptidases that have similar mechanisms to that of the deubiquitinating enzymes.
Within some species, the recognition and destruction of sperm mitochondria through a mechanism involving ubiquitin is responsible for sperm mitochondria's disposal after fertilization occurs.
Human proteins containing ubiquitin domain
ANUBL1; BAG1BAG1
BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the BAG1 gene.BAG gene has been implicated in age related neurodegenerative diseases as Alzheimer's...
; BAT3; DDI1; DDI2; FAU
FAU (gene)
40S ribosomal protein S30 is a protein that in humans is encoded by the FAU gene.-Further reading:...
; HERPUD1
HERPUD1
Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein is a protein that in humans is encoded by the HERPUD1 gene.-Interactions:HERPUD1 has been shown to interact with UBQLN1 and UBQLN2.-Further reading:...
; HERPUD2;
HOPS
Hops
Hops are the female flower clusters , of a hop species, Humulus lupulus. They are used primarily as a flavoring and stability agent in beer, to which they impart a bitter, tangy flavor, though hops are also used for various purposes in other beverages and herbal medicine...
; IKBKB; ISG15
ISG15
Interferon-induced 17 kDa protein is a protein that in humans is encoded by the ISG15 gene. ISG15 shares several common properties with other ubiquitin-like molecules , but its activity is tightly regulated by specific signaling pathways that have a role in innate immunity...
; LOC391257; MIDN; NEDD8
NEDD8
NEDD8 is a protein that in humans is encoded by the NEDD8 gene. This ubiquitin-like protein , which becomes covalently conjugated to a limited number of cellular proteins in a manner analogous to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin...
; OASL
OASL
59 kDa 2'-5'-oligoadenylate synthetase-like protein is an enzyme that in humans is encoded by the OASL gene.-Further reading:...
; PARK2;
RAD23A
RAD23A
UV excision repair protein RAD23 homolog A is a protein that in humans is encoded by the RAD23A gene.-Interactions:RAD23A has been shown to interact with PSMD4, Sequestosome 1 and Ataxin 3.-Further reading:...
; RAD23B
RAD23B
UV excision repair protein RAD23 homolog B is a protein that in humans is encoded by the RAD23B gene.-Interactions:RAD23B has been shown to interact with PSMD4 and Ataxin 3.-Further reading:...
; RPS27A
RPS27A
40S ribosomal protein S27a is a protein that in humans is encoded by the RPS27A gene.-Further reading:...
; SACS
SACS
SACS may refer to:* St Andrew's Cathedral School, an Anglican school in Sydney, Australia* The South African College Schools, a school in Cape Town, South Africa...
; SF3A1
SF3A1
Splicing factor 3 subunit 1 is a protein that in humans is encoded by the SF3A1 gene.-Interactions:SF3A1 has been shown to interact with SF3A3 and CDC5L.-Further reading:...
; SUMO1; SUMO2
SUMO2
Small ubiquitin-related modifier 2 is a protein that in humans is encoded by the SUMO2 gene.-Further reading:...
; SUMO3
SUMO3
Small ubiquitin-related modifier 3 is a protein that in humans is encoded by the SUMO3 gene.-Interactions:SUMO3 has been shown to interact with ARNTL and Thymine-DNA glycosylase.-Further reading:...
;
SUMO4
SUMO4
Small ubiquitin-related modifier 4 is a protein that in humans is encoded by the SUMO4 gene.-Further reading:...
; TMUB1; TMUB2
TMUB2
Transmembrane and ubiquitin-like domain-containing protein 2 is a protein that in humans is encoded by the TMUB2 gene.-Further reading:...
; UBA52
UBA52
60S ribosomal protein L40 is a protein that in humans is encoded by the UBA52 gene.-Further reading:...
; UBB
Ubiquitin B
Ubiquitin is a protein that in humans is encoded by the UBB gene.- Function :Ubiquitin, one of the most conserved proteins known. Ubiquitin is required for ATP-dependent, non-lysosomal intracellular protein degradation of abnormal proteins and normal proteins with a rapid turnover...
; UBC
Ubiquitin C
Ubiquitin is a protein that in humans is encoded by the UBC gene.-Interactions:Ubiquitin C has been shown to interact with SCNN1A, SCNN1G, Parkin , P70-S6 Kinase 1, TRAF6, HDAC3, SFPQ, S100A10, Mothers against decapentaplegic homolog 3, NOTCH1, HIF1A, Epidermal growth factor receptor, E2F1,...
; UBD; UBFD1;
UBL4; UBL4A
UBL4A
Ubiquitin-like protein 4A is a protein that in humans is encoded by the UBL4A gene.-Further reading:...
; UBL4B; UBL7; UBLCP1; UBQLN1
UBQLN1
Ubiquilin-1 is a protein that in humans is encoded by the UBQLN1 gene.Ubiquilins contain a N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain...
; UBQLN2
UBQLN2
Ubiquilin-2 is a protein that in humans is encoded by the UBQLN2 gene.- Function :This gene encodes a ubiquitin-like protein that shares high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain a N-terminal ubiquitin-like domain and a C-terminal...
; UBQLN3;
UBQLN4; UBQLNL; UBTD1; UBTD2; UHRF1
UHRF1
Ubiquitin-like, containing PHD and RING finger domains, 1, also known as UHRF1, is a protein which in humans is encoded by the UHRF1 gene.- Function :...
; UHRF2
UHRF2
E3 ubiquitin-protein ligase UHRF2 is an enzyme that in humans is encoded by the UHRF2 gene.-Further reading:...
;
See also
- AutophagyAutophagyIn cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...
- AutophaginAutophaginAutophagin-1 is a unique cysteine protease responsible for the cleavage of the carboxyl terminus of Atg8/Apg8/Aut7, a reaction essential for its lipidation during autophagy...
- ERADERADEndoplasmic-reticulum-associated protein degradation designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome....
- SUMO proteinSUMO proteinSmall Ubiquitin-like Modifier or SUMO proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function...
- SUMO enzymesSUMO enzymesSUMO enzymatic cascade catalyzes the dynamic posttranslational modification process of sumoylation...
- Ubiquitin ligaseUbiquitin ligaseA ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
External links
Academic
- UniProt entry for ubiquitin
- UbiPred — server for the prediction of ubiquitylation sites
- Ubiquitin Web-page
- 7.340 Ubiquitination: The Proteasome and Human Disease MIT OpenCourseWare. Notes from MIT course.
Commercial
- Enzo Life Sciences : Ubiquitin and Proteasome Research Products
- Boston Biochem : Ubiquitin and Ubiquitin-like Research Products
- Progenra Inc. : Ubiquitin-based Biotechnology Corporation