Cyclin

Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase (Cdk) enzymes.^[1]

Function

Expression of human cyclins through the cell cycle.

Cyclins were originally named because their concentration varies in a cyclical fashion during the cell cycle. (Note that the cyclins are now classified according to their conserved cyclin box structure, and not all these cyclins alter in level through the cell cycle.^[2]) The oscillations of the cyclins, namely fluctuations in cyclin gene expression and destruction by the ubiquitin mediated proteasome pathway, induce oscillations in Cdk activity to drive the cell cycle. A cyclin forms a complex with Cdk, which begins to activate the Cdk, but the complete activation requires phosphorylation, as well. Complex formation results in activation of the Cdk active site. Cyclins themselves have no enzymatic activity but have binding sites for some substrates and target the Cdks to specific subcellular locations.^[2]

They were discovered by R. Timothy Hunt in 1982 while studying the cell cycle of sea urchins.^[3][4]

In an interview for "The Life Scientific" (aired on 13/12/2011) hosted by Jim Al-Khalili, R. Timothy Hunt explained that the name "cyclin" was originally named after his hobby cycling. It was only after the naming did its importance in the cell cycle become apparent. As it was appropriate the name stuck.^[5] R. Timothy Hunt: "By the way, the name cyclin, which I coined, was really a joke, it's because I liked cycling so much at the time, but they did come and go in the cell..."^[5]

Cyclins, when bound with the dependent kinases, such as the p34 (cdc2) or cdk1 proteins, form the maturation-promoting factor. MPFs activate other proteins through phosphorylation. These phosphorylated proteins, in turn, are responsible for specific events during cycle division such as microtubule formation and chromatin remodeling. Cyclins can be divided into four classes based on their behavior in the cell cycle of vertebrate somatic cells and yeast cells: G1/S cyclins, S cyclins, G2 cyclins, M cyclins. This division is useful when talking about most cell cycles, but it is not universal as some cyclins have different functions or timing in different cell types.

G1/S Cyclins rise in late G1 and fall in early S phase. The Cdk- G1/S cyclin complex begins to induce the initial processes of DNA replication, primarily by arresting systems that prevent S phase Cdk activity in G1. The cyclins also promote other activities to progress the cell cycle, like centrosome duplication in vertebrates or spindle pole body in yeast. The rise in presence of G1/S cyclins is paralleled by a rise in S cyclins.

S cyclins bind to Cdk and the complex directly induces DNA replication. The levels of S cyclins remain high, not only throughout S phase, but through G2 and early mitosis as well to promote early events in mitosis.

M cyclin concentrations rise as the cell begins to enter mitosis and the concentrations peak at metaphase. Cell changes in the cell cycle like the assembly of mitotic spindles and alignment of sister-chromatids along the spindles are induced by M cyclin- Cdk complexes. The destruction of M cyclins during metaphase and anaphase, after the Spindle Assembly Checkpoint is satisfied, causes the exit of mitosis and cytokinesis.^[6]

G1 cyclins do not behave like the other cyclins, in that the concentrations increase gradually (with no oscillation), throughout the cell cycle based on cell growth and the external growth-regulatory signals. The presence of G cyclins coordinate cell growth with the entry to a new cell cycle.

Domain structure

Cyclins are generally very different from each other in primary structure, or amino acid sequence. However, all members of the cyclin family are similar in 100 amino acids that make up the cyclin box. Cyclins contain two domains of similar all-α fold, the first located at the N-terminus and the second at the C-terminus. All cyclins are believed to contain a similar tertiary structure of two compact domains of 5 α helices. The first of which is the conserved cyclin box, outside of which cyclins are divergent. For example, the amino-terminal regions of S and M cyclins contain short destruction-box motifs that target these proteins for proteolysis in mitosis.

Cyclin, N-terminal domain Structure of bovine cyclin A.[7] Identifiers Symbol Cyclin_N Pfam PF00134 Pfam clan CL0065 InterPro IPR006671 PROSITE PDOC00264 SCOP 1vin SUPERFAMILY 1vin Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Cyclin, C-terminal domain Structure of CDK2-cyclin A/indirubin-5-sulphonate.[8] Identifiers Symbol Cyclin_C Pfam PF02984 Pfam clan CL0065 InterPro IPR004367 PROSITE PDOC00264 SCOP 1vin SUPERFAMILY 1vin Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

K cyclin, C terminal structure of a p18(ink4c)-cdk6-k-cyclin ternary complex Identifiers Symbol K-cyclin_vir_C Pfam PF09080 InterPro IPR015164 SCOP 1g3n SUPERFAMILY 1g3n Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Types

There are several different cyclins that are active in different parts of the cell cycle and that cause the Cdk to phosphorylate different substrates. There are also several "orphan" cyclins for which no Cdk partner has been identified. For example, cyclin F is an orphan cyclin that is essential for G₂/M transition.^[9][10] A study in C. elegans revealed the specific roles of mitotic cyclins.^[11][12] Notably, recent studies have shown that cyclin A creates a cellular environment that promotes microtubule detachment from kinetochores in prometaphase to ensure efficient error correction and faithful chromosome segregation. Cells must separate their chromosomes precisely, an event that relies on the bi-oriented attachment of chromosomes to spindle microtubules through specialized structures called kinetochores. In the early phases of division, there are numerous errors in how kinetochores bind to spindle microtubules. The unstable attachments promote the correction of errors by causing a constant detachment, realignment and reattachment of microtubules from kinetochores in the cells as they try to find the correct attachment. Protein cyclin A governs this process by keeping the process going until the errors are eliminated. In normal cells, persistent cyclin A expression prevents the stabilization of microtubules bound to kinetochores even in cells with aligned chromosomes. As levels of cyclin A decline, microtubule attachments become stable, allowing the chromosomes to be divided correctly as cell division proceeds. In contrast, in cyclin A-deficient cells, microtubule attachments are prematurely stabilized. Consequently, these cells may fail to correct errors, leading to higher rates of chromosome mis-segregation.^[13]

Main groups

There are two main groups of cyclins:

• G₁/S cyclins – essential for the control of the cell cycle at the G₁/S transition,
  • Cyclin A / CDK2 – active in S phase.
  • Cyclin D / CDK4, Cyclin D / CDK6, and Cyclin E / CDK2 – regulates transition from G₁ to S phase.
• G₂/M cyclins – essential for the control of the cell cycle at the G2/M transition (mitosis). G₂/M cyclins accumulate steadily during G₂ and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase).
  • Cyclin B / CDK1 – regulates progression from G₂ to M phase.

Subtypes

Specific cyclin subtypes include:

Species	G1	G1/S	S	M
S. cerevisiae	Cln3 (Cdk1)	Cln 1,2 (Cdk1)	Clb 5,6 (Cdk1)	Clb 1,2,3,4 (Cdk 1)
S. pombe	Puc1? (Cdk1)	Puc1, Cig1? (Cdk1)	Cig2, Cig1? (Cdk1)	Cdc13 (Cdk1)
D. melanogaster	cyclin D (Cdk4)	cyclin E (Cdk2)	cyclin E, A (Cdk2,1)	cyclin A, B, B3 (Cdk1)
X. laevis	either not known or not present	cyclin E (Cdk2)	cyclin E, A (Cdk2,1)	cyclin A, B, B3 (Cdk1)
H. sapiens	cyclin D 1,2,3 (Cdk4, Cdk6)	cyclin E (Cdk2)	cyclin A (Cdk2, Cdk1)	cyclin B (Cdk1)

family	members
A	CCNA1, CCNA2
B	CCNB1, CCNB2, CCNB3
C	CCNC
D	CCND1, CCND2, CCND3
E	CCNE1, CCNE2
F	CCNF
G	CCNG1, CCNG2
H	CCNH
I	CCNI, CCNI2
J	CCNJ, CCNJL
K	CCNK
L	CCNL1, CCNL2
O	CCNO
T	CCNT1, CCNT2
Y	CCNY, CCNYL1, CCNYL2, CCNYL3

Other proteins containing this domain

In addition, the following human proteins contain a cyclin domain:

CABLES2, CNTD1, CNTD2

History

Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of cyclin and cyclin-dependent kinase.^[14]

References

1. Galderisi U, Jori FP, Giordano A (August 2003). "Cell cycle regulation and neural differentiation". Oncogene 22 (33): 5208–19. doi:10.1038/sj.onc.1206558. PMID 12910258.
2. Morgan, DO (2007) 'The Cell Cycle: Principles of Control, Oxford University Press
3. Evans et al., 1983, Cell 33, p389-396
4. http://nobelprize.org/nobel_prizes/medicine/laureates/2001/hunt-autobio.html
5. "The Life Scientific". BBC Radio 4. BBC. Retrieved 13 December 2011.
6. Clute and Pines, (1999) Nature Cell Biology, 1, p82-87
7. Brown NR, Noble ME, Endicott JA; et al. (November 1995). "The crystal structure of cyclin A". Structure 3 (11): 1235–47. doi:10.1016/S0969-2126(01)00259-3. PMID 8591034.
8. Davies TG, Tunnah P, Meijer L; et al. (May 2001). "Inhibitor binding to active and inactive CDK2: the crystal structure of CDK2-cyclin A/indirubin-5-sulphonate". Structure 9 (5): 389–97. doi:10.1016/S0969-2126(01)00598-6. PMID 11377199.
9. Fung TK, Poon RY (2005). "A roller coaster ride with the mitotic cyclins". Semin. Cell Dev. Biol. 16 (3): 335–42. doi:10.1016/j.semcdb.2005.02.014. PMID 15840442.
10. Gerald Karp, (2007). Cell and Molecular Biology: Concepts and Experiments. New York: Wiley. pp. 148, 165–170, and 624–664. ISBN 0-470-04217-6.
11. van der Voet, Monique; Lorson, Monique; Srinivasan, Dayalan G.; Bennett, Karen L.; van den Heuvel, Sander (2009). "C. elegans mitotic cyclins have distinct as well as overlapping functions in chromosome segregation". Cell Cycle 8 (24): 4091–4102. doi:10.4161/cc.8.24.10171. ISSN 1538-4101.
12. Rahman, Mohammad M.; Kipreos, Edward (2010). "The specific roles of mitotic cyclins revealed". Cell Cycle 9 (1): 22–27. doi:10.4161/cc.9.1.10577. ISSN 1538-4101.
13. Nature Reviews Molecular Cell Biology (2013) doi:10.1038/nrm3680
14. "The Nobel Prize in Physiology or Medicine 2001". The Nobel Foundation. Retrieved 2009-03-15.

External links

• Eukaryotic Linear Motif resource motif class LIG_CYCLIN_1

Further reading

• Monty Krieger; Matthew P Scott; Matsudaira, Paul T.; Lodish, Harvey F.; Darnell, James E.; Lawrence Zipursky; Kaiser, Chris; Arnold Berk (2004). Molecular cell biology (Fifth ed.). New York: W.H. Freeman and CO. ISBN 0-7167-4366-3.

This article incorporates text from the public domain Pfam and InterPro IPR006671