Cullin
Encyclopedia
Cullins are a family of hydrophobic protein
s providing a scaffold for ubiquitin ligase
s (E3). All eukaryotes appear to have cullins. They combine with RING proteins
to form Cullin-RING ubiquitin ligases (CRLs) that are highly diverse and play a role in a myriad of cellular processes.
Human genome contains seven cullin genes:
CUL1, 2, 3, 4A, 4B, 5 and 7 each form part of a multi-subunit ubiquitin
complex
.
Cullin-RING ubiquitin ligase
s (CRLs), such as Cul1 (SCF) play an essential role in targeting protein
s for ubiquitin-mediated destruction; as such, they are diverse in terms of composition and function, regulating many different processes from glucose
sensing and DNA replication
to limb patterning and circadian rhythms. The catalytic core of CRLs consists of a RING protein and a cullin family member. For Cul1, the C-terminal cullin-homology domain binds the RING protein. The RING protein appears to function as a docking site for ubiquitin-conjugating enzyme
s (E2s). Other proteins contain a cullin-homology domain, such as the APC2 subunit of the anaphase-promoting complex/cyclosome and the p53
cytoplasm
ic anchor PARC
; both APC2 and PARC have ubiquitin ligase activity. The N-terminal region of cullins is more variable, and is used to interact
with specific adaptor protein
s.
With the exception of APC2, each member of the cullin family is modified by Nedd8
and several cullins function in Ubiquitin-dependent proteolysis, a process in which the 26S proteasome
recognises and subsequently degrades a target protein tagged with K48-linked poly-ubiquitin chain
s. Nedd8/Rub1 is a small ubiquitin-like protein, which was originally found to be conjugated to Cdc53, a cullin component of the SCF (Skp1-Cdc53/CUL1-F-box protein) E3 Ub ligase complex
in Saccharomyces cerevisiae
(Baker's yeast), and Nedd8 modification has now emerged as a regulatory pathway of fundamental importance for cell cycle
control and for embryogenesis
in metazoans. The only identified Nedd8 substrates
are cullins. Neddylation
results in covalent conjugation of a Nedd8 moiety onto a conserved
cullin lysine
residue
.
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...
s providing a scaffold for 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 (E3). All eukaryotes appear to have cullins. They combine with RING proteins
RING finger domain
In 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...
to form Cullin-RING ubiquitin ligases (CRLs) that are highly diverse and play a role in a myriad of cellular processes.
Human genome contains seven cullin genes:
- CUL1CUL1Cullin 1, also known as CUL1, is a human protein and gene from cullin family.This protein plays an important role in protein degradation and protein ubiquitination....
, part of SCF complexSCF complexSkp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation... - CUL2CUL2Cullin-2 is a protein that in humans is encoded by the CUL2 gene.-Interactions:CUL2 has been shown to interact with DCUN1D1, SAP130, CAND1, RBX1, TCEB2 and Von Hippel-Lindau tumor suppressor.-Further reading:...
, part of ECS complex (Elongin C - CUL2 - SOCS-box) - CUL3CUL3Cullin-3 is a protein that in humans is encoded by the CUL3 gene.-Interactions:CUL3 has been shown to interact with KLHL12, CAND1, KEAP1, DCUN1D1 and Cyclin E1.-Further reading:...
, part of CUL3-BTB complex - CUL4ACUL4ACullin-4A is a protein that in humans is encoded by the CUL4A gene.-Interactions:CUL4A has been shown to interact with Merlin, DDB2, CAND1, RBX1, DDB1 and P21.-Further reading:...
- CUL4BCUL4BCullin-4B is a protein that in humans is encoded by the CUL4B gene.-Interactions:CUL4B has been shown to interact with DDB2, CAND1 and DDB1.-Further reading:...
- CUL5CUL5Cullin-5 is a protein that in humans is encoded by the CUL5 gene.-Discovery:The mammalian gene product was originally discovered by expression cloning, due to the protein's ability to mobilize intracellular calcium in response to the peptide hormone arginine vasopressin. It was first titled...
- CUL7CUL7Cullin-7 is a protein that in humans is encoded by the CUL7 gene.-External Links:* *...
- a more distant member called ANAPC2ANAPC2Anaphase-promoting complex subunit 2 is an enzyme that in humans is encoded by the ANAPC2 gene.A large protein complex, termed the anaphase-promoting complex , or the cyclosome, promotes metaphase-anaphase transition by ubiquitinating its specific substrates such as mitotic cyclins and anaphase...
, part of Anaphase-promoting complexAnaphase-promoting complexAnaphase-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...
CUL1, 2, 3, 4A, 4B, 5 and 7 each form part of a multi-subunit 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...
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...
.
Cullin-RING 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 (CRLs), such as Cul1 (SCF) play an essential role in targeting 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...
s for ubiquitin-mediated destruction; as such, they are diverse in terms of composition and function, regulating many different processes from glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
sensing and DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
to limb patterning and circadian rhythms. The catalytic core of CRLs consists of a RING protein and a cullin family member. For Cul1, the C-terminal cullin-homology domain binds the RING protein. The RING protein appears to function as a docking site for ubiquitin-conjugating enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s (E2s). Other proteins contain a cullin-homology domain, such as the APC2 subunit of the anaphase-promoting complex/cyclosome and the p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic anchor PARC
PARC
PARC or Parc may refer to:* PARC , the Palo Alto Research Center * PARC Management, a theme park and entertainment venue operator...
; both APC2 and PARC have ubiquitin ligase activity. The N-terminal region of cullins is more variable, and is used to interact
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...
with specific adaptor protein
Adaptor protein
Signal transducing adaptor proteins are proteins which are accessory to main proteins in a signal transduction pathway. These proteins tend to lack any intrinsic enzymatic activity themselves but instead mediate specific protein–protein interactions that drive the formation of protein complexes...
s.
With the exception of APC2, each member of the cullin family is modified by 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...
and several cullins function in Ubiquitin-dependent proteolysis, a process in which the 26S 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...
recognises and subsequently degrades a target protein tagged with K48-linked poly-ubiquitin chain
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
s. Nedd8/Rub1 is a small ubiquitin-like protein, which was originally found to be conjugated to Cdc53, a cullin component of the SCF (Skp1-Cdc53/CUL1-F-box protein) E3 Ub ligase 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 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...
(Baker's yeast), and Nedd8 modification has now emerged as a regulatory pathway of fundamental importance for cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
control and for embryogenesis
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
in metazoans. The only identified Nedd8 substrates
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...
are cullins. Neddylation
Neddylation
Neddylation is the process by which the ubiquitin like protein Nedd8 is conjugated to its target proteins. This process is analogous to ubiquitination, although relies on its own E1 and E2 enzymes...
results in covalent conjugation of a Nedd8 moiety onto a conserved
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
cullin 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
Residue (chemistry)
In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....
.
External links
- Cullin family - Sanger InstituteSanger InstituteThe Wellcome Trust Sanger Institute is a non-profit, British genomics and genetics research institute, primarily funded by the Wellcome Trust....
website.