Ubiquitin-conjugating enzyme
Encyclopedia
Ubiquitin-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 amino acid
s, to a lysine
residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the ATP
-dependent unfolding
of the target protein that allows passage into the proteasome's 20S core particle, where protease
s degrade the target into short peptide
fragments for recycling by the cell
.
or E1 first activates the ubiquitin by covalently attaching the molecule to its active site
cysteine
residue. The activated ubiquitin is then transferred to an E2 cysteine. Once conjugated to ubiquitin, the E2 molecule binds one of several ubiquitin ligase
s or E3s via a structurally conserved binding
region. The E3 molecule is responsible for binding the target protein substrate
and transferring the ubiquitin from the E2 cysteine to a lysine residue on the target protein.
A particular cell usually contains only a few types of E1 molecule, a greater diversity of E2s, and a very large variety of E3s. The E3 molecules responsible for substrate identification and binding are thus the mechanisms of substrate specificity in proteasomal degradation. Each type of E2 can associate with many E3s.
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...
for degradation via 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...
.The ubiquitination process covalently attaches ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
, a short protein 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, to a 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....
residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the 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 unfolding
Denaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
of the target protein that allows passage into the proteasome's 20S core particle, where protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s degrade the target into short 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...
fragments for recycling by the 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....
.
Relationships
A ubiquitin-activating enzymeUbiquitin-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...
or E1 first activates the ubiquitin by covalently attaching the molecule to its active site
Active site
In 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
Cysteine
Cysteine 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. The activated ubiquitin is then transferred to an E2 cysteine. Once conjugated to ubiquitin, the E2 molecule binds one of several ubiquitin ligase
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...
s or E3s via a structurally conserved binding
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
region. The E3 molecule is responsible for binding the target protein 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...
and transferring the ubiquitin from the E2 cysteine to a lysine residue on the target protein.
A particular cell usually contains only a few types of E1 molecule, a greater diversity of E2s, and a very large variety of E3s. The E3 molecules responsible for substrate identification and binding are thus the mechanisms of substrate specificity in proteasomal degradation. Each type of E2 can associate with many E3s.
Isozymes
The following human genes encode ubiquitin-conjugating enzymes:- UBE2AUBE2AUbiquitin-conjugating enzyme E2 A is a protein that in humans is encoded by the UBE2A gene.-Interactions:UBE2A has been shown to interact with RAD18 and P53.-Further reading:...
- UBE2BUBE2BUbiquitin-conjugating enzyme E2 B is a protein that in humans is encoded by the UBE2B gene.-Further reading:...
- UBE2CUBE2CUbiquitin-conjugating enzyme E2 C is a protein that in humans is encoded by the UBE2C gene.-Further reading:...
- UBE2D1UBE2D1Ubiquitin-conjugating enzyme E2 D1 is a protein that in humans is encoded by the UBE2D1 gene.-Interactions:UBE2D1 has been shown to interact with BARD1, UBE3A and BRCA1.-Further reading:...
, UBE2D2UBE2D2Ubiquitin-conjugating enzyme E2 D2 is a protein that in humans is encoded by the UBE2D2 gene.-Interactions:UBE2D2 has been shown to interact with PJA1, Baculoviral IAP repeat-containing protein 3, PJA2, UBE3A and NEDD4.-Further reading:...
, UBE2D3UBE2D3Ubiquitin-conjugating enzyme E2 D3 is a protein that in humans is encoded by the UBE2D3 gene.-Further reading:...
, UBE2D4 (the latter putative) - UBE2E1UBE2E1Ubiquitin-conjugating enzyme E2 E1 is a protein that in humans is encoded by the UBE2E1 gene.-Interactions:UBE2E1 has been shown to interact with Ataxin 1 and NEDD4.-Further reading:...
, UBE2E2UBE2E2Ubiquitin-conjugating enzyme E2 E2 is a protein that in humans is encoded by the UBE2E2 gene.-Further reading:...
, UBE2E3UBE2E3Ubiquitin-conjugating enzyme E2 E3 is a protein that in humans is encoded by the UBE2E3 gene.-Further reading:... - UBE2F (putative)
- UBE2G1UBE2G1Ubiquitin-conjugating enzyme E2 G1 is a protein that in humans is encoded by the UBE2G1 gene.-Further reading:...
, UBE2G2UBE2G2Ubiquitin-conjugating enzyme E2 G2 is a protein that in humans is encoded by the UBE2G2 gene.-Further reading:... - UBE2HUBE2HUbiquitin-conjugating enzyme E2 H is a protein that in humans is encoded by the UBE2H gene.-Further reading:...
- UBE2IUBE2ISUMO-conjugating enzyme UBC9 is a protein that in humans is encoded by the UBE2I gene.-Interactions:UBE2I has been shown to interact with WT1, TOP1, RAD51, Activating transcription factor 2, PIAS1, SALL1, FHIT, RANBP2, Protein inhibitor of activated STAT2, DNMT3A, DNMT3B, Small ubiquitin-related...
- UBE2J1UBE2J1Ubiquitin-conjugating enzyme E2 J1 is a protein that in humans is encoded by the UBE2J1 gene.-Further reading:...
, UBE2J2 - UBE2K
- UBE2L3UBE2L3Ubiquitin-conjugating enzyme E2 L3 is a protein that in humans is encoded by the UBE2L3 gene.-Interactions:UBE2L3 has been shown to interact with UBOX5, ARIH1, Cbl gene, UBE3A and NEDD4.-Further reading:...
, UBE2L6UBE2L6Ubiquitin/ISG15-conjugating enzyme E2 L6 is a protein that in humans is encoded by the UBE2L6 gene.-Further reading:...
; (UBE2L1, UBE2L2, UBE2L4 are pseudogenes) - UBE2MUBE2MNEDD8-conjugating enzyme Ubc12 is a protein that in humans is encoded by the UBE2M gene.-Interactions:UBE2M has been shown to interact with NEDD8, PRKAR1A and UBA3.-Further reading:...
- UBE2NUBE2NUbiquitin-conjugating enzyme E2 N is a protein that in humans is encoded by the UBE2N gene.-Interactions:UBE2N has been shown to interact with Aurora A kinase, TRAF2, TRAF6, HLTF and UBE2V1.-Further reading:...
- UBE2OUBE2OUbiquitin-conjugating enzyme E2 O is a protein that in humans is encoded by the UBE2O gene.-Further reading:...
- UBE2Q1, UBE2Q2
- UBE2R1 (CDC34), UBE2R2UBE2R2Ubiquitin-conjugating enzyme E2 R2 is a protein that in humans is encoded by the UBE2R2 gene.-Further reading:...
- UBE2S
- UBE2T (putative)
- UBE2U (putative)
- UBE2V1UBE2V1Ubiquitin-conjugating enzyme E2 variant 1 is a protein that in humans is encoded by the UBE2V1 gene.-Further reading:...
, UBE2V2UBE2V2Ubiquitin-conjugating enzyme E2 variant 2 is a protein that in humans is encoded by the UBE2V2 gene.-Further reading:... - UBE2W (putative)
- UBE2Z
- ATG3
- BIRC6BIRC6Baculoviral IAP repeat-containing protein 6 is a protein that in humans is encoded by the BIRC6 gene.-Further reading:...
- UFC1