Cullins are a family of hydrophobic

scaffold protein In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them i ...

s which provide support for

ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquit ...

s (E3). All

eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacter ...

s 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 myriad cellular processes, most notably protein degradation by

ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...

. The human genome contains eight cullin genes * CUL1, part of

SCF complex Skp, Cullin, F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has impo ...

CUL2 Cullin-2 is a protein that in humans is encoded by the ''CUL2'' gene. Interactions CUL2 has been shown to interact with: * CAND1, * DCUN1D1, * RBX1, * SAP130, * TCEB2 and * Von Hippel-Lindau tumor suppressor The term ''von'' () ...

, part of ECS complex ( Elongin C - CUL2 - SOCS-box) *

CUL3 Cullin 3 is a protein that in humans is encoded by the ''CUL3'' gene. Cullin 3 protein belongs to the family of cullins which in mammals contains eight proteins (Cullin 1, Cullin 2, Cullin 3, Cullin 4A, Cullin 4B, Cullin 5, Cullin 7 and Cullin 9) ...

, part of CUL3-BTB complex *

CUL4A Cullin-4A is a protein that in humans is encoded by the ''CUL4A'' gene. CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chr ...

CUL4B Cullin-4B is a protein that in humans is encoded by the ''CUL4B'' gene which is located on the X chromosome. CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in ...

CUL5 Cullin-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 ...

CUL7 Cullin-7 is a RING-E3 ligase protein that in humans is encoded by the ''CUL7'' gene. Clinical significance It is associated with 3-M syndrome. Interactions CUL7 has been shown to interact with RBX1. References Further reading * * * * * ...

CUL9 Cullin-9 is a protein that in humans is encoded by the ''CUL9'' gene. Interactions PARC (gene) has been shown to interact with P53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related p ...

, also known as PARC There is also a more distant member called

ANAPC2 Anaphase-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 (APC), or the cyclosome, promotes metaphase-anaphase transition by ubiquitinating ...

(or APC2), part of the

Anaphase-promoting complex Anaphase-promoting complex (also called the cyclosome or APC/C) 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 cull ...

. CUL1, 2, 3, 4A, 4B, 5 and 7 each form part of a multi-subunit

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...

complex Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...

Cullin-RING ubiquitin ligases

Cullin-RING ubiquitin

ligase In biochemistry, a ligase is an enzyme that can catalyze the joining (ligation) of two large molecules by forming a new chemical bond. This is typically via hydrolysis of a small pendant chemical group on one of the larger molecules or the enzym ...

s (CRLs), such as Cul1 (SCF) play an essential role in targeting

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s for ubiquitin-mediated destruction; as such, they are diverse in terms of composition and function, regulating many different processes from

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

sensing and

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritan ...

to limb patterning and

circadian rhythms A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...

. The

catalytic Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

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 Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s (E2s). Other

s contain a cullin-homology domain, such as

, also known as

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

ic anchor PARC, and the

subunit of the anaphase-promoting complex/cyclosome; both CUL9 and ANAPC2 have ubiquitin ligase activity. The N-terminal region of cullins is more variable, and is used to

interact Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...

with specific adaptor proteins.

Modification by NEDD8

With the exception of ANAPC2, each member of the cullin family is modified by

Nedd8 NEDD8 is a protein that in humans is encoded by the ''NEDD8'' gene. (in ''saccharomyces cerevisiae'' this protein is known as Rub1) This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a proc ...

and several cullins function in Ubiquitin-dependent proteolysis, a process in which the 26S

proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by whi ...

recognises and subsequently degrades a target protein tagged with K48-linked poly-ubiquitin

chain A chain is a serial assembly of connected pieces, called links, typically made of metal, with an overall character similar to that of a rope in that it is flexible and curved in compression but linear, rigid, and load-bearing in tension. ...

s. Nedd8/Rub1 is a small

ubiquitin-like protein Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell, usually with a regulatory function. The UBL protein family derives its name from the first member of the class ...

, which was originally found to be conjugated to Cdc53, a cullin component of the SCF (Skp1-Cdc53/CUL1-F-box protein) E3 Ub ligase

in ''

Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have b ...

'' (Baker's yeast), and Nedd8 modification has now emerged as a regulatory pathway of fundamental importance for

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...

control and for

embryogenesis An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

metazoan Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in ...

s. The only identified Nedd8 substrates are cullins. Neddylation results in

covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...

conjugation of a Nedd8 moiety onto a conserved cullin

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated − ...

residue.

References

External links

Cullin family
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Sanger Institute The Wellcome Sanger Institute, previously known as The Sanger Centre and Wellcome Trust Sanger Institute, is a non-profit British genomics and genetics research institute, primarily funded by the Wellcome Trust. It is located on the Wellcome Ge ...

website. * Protein families {{protein-stub