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190  structures 547  species 6  interactions 6213  sequences 86  architectures

Family: Cyclin_N (PF00134)

Summary: Cyclin, N-terminal domain

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This is the Wikipedia entry entitled "Cyclin". More...

Cyclin Edit Wikipedia article

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[edit]

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.[3]

They were discovered by R. Timothy Hunt in 1982 while studying the cell cycle of sea urchins.[4][5]

In an interview for the BBC4 documentary "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.[6] R. Timothy Hunt: "By the way, the name cyclin, which I coined, was really a joke, it's because I like cycling so much at the time but they did come and go in the cell..." [7]

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, M cyclins, G1 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.[8]

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[edit]

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
PDB 1vin EBI.jpg
Structure of bovine cyclin A.[9]
Identifiers
Symbol Cyclin_N
Pfam PF00134
Pfam clan CL0065
InterPro IPR006671
PROSITE PDOC00264
SCOP 1vin
SUPERFAMILY 1vin
Cyclin, C-terminal domain
PDB 1e9h EBI.jpg
Structure of CDK2-cyclin A/indirubin-5-sulphonate.[10]
Identifiers
Symbol Cyclin_C
Pfam PF02984
Pfam clan CL0065
InterPro IPR004367
PROSITE PDOC00264
SCOP 1vin
SUPERFAMILY 1vin
K cyclin, C terminal
PDB 1g3n EBI.jpg
structure of a p18(ink4c)-cdk6-k-cyclin ternary complex
Identifiers
Symbol K-cyclin_vir_C
Pfam PF09080
InterPro IPR015164
SCOP 1g3n
SUPERFAMILY 1g3n

Types[edit]

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.[11][12] A study in C. elegans revealed the specific roles of mitotic cyclins.[13][14] 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.[15]

Main groups[edit]

There are two main groups of cyclins:

  • G1/S cyclins – essential for the control of the cell cycle at the G1/S transition,
  • 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[edit]

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 (Cdk4,6) cyclin E (Cdk2) cyclin A (Cdk2,1) 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[edit]

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

CABLES2, CNTD1, CNTD2

History[edit]

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.[16]

References[edit]

  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. ^ (Morgan, D.O. (2007) The Cell Cycle: Principles of Control. Oxford University Press.
  4. ^ Evans et al., 1983, Cell 33, p389-396
  5. ^ http://nobelprize.org/nobel_prizes/medicine/laureates/2001/hunt-autobio.html
  6. ^ "The Life Scientific". BBC Radio 4. BBC. Retrieved 13 December 2011. 
  7. ^ "The Life Scientific". BBC Radio 4. Retrieved 13 December 2012. 
  8. ^ Clute and Pines, (1999) Nature Cell Biology, 1, p82-87
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ Nature Reviews Molecular Cell Biology (2013) doi:10.1038/nrm3680
  16. ^ "The Nobel Prize in Physiology or Medicine 2001". The Nobel Foundation. Retrieved 2009-03-15. 

External links[edit]

Further reading[edit]

  • 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

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Cyclin, N-terminal domain Provide feedback

Cyclins regulate cyclin dependent kinases (CDKs). P22674 is a Uracil-DNA glycosylase that is related to other cyclins [4]. Cyclins contain two domains of similar all-alpha fold, of which this family corresponds with the N-terminal domain.

Literature references

  1. Gibson TJ, Thompson JD, Blocker A, Kouzarides T; , Nucleic Acids Res 1994;22:946-952.: Evidence for a protein domain superfamily shared by the cyclins, TFIIB and RB/p107. PUBMED:8152925 EPMC:8152925

  2. Brown NR, Noble MEM, Endicott JA, Garman EF, Wakatsuki S, Mitchell E, Rasmussen B, Hunt T, Johnson LN; , Structure. 1995;3:1235-1247.: The crystal structure of cyclin A PUBMED:8591034 EPMC:8591034

  3. Russo AA, Jeffrey PD, Pavletich NP; , Nat Struct Biol. 1996;3:696-700.: Structural basis of cyclin-dependant kinase activation by phosphorylation. PUBMED:8756328 EPMC:8756328

  4. Muller SJ, Caradonna S; , Biochim Biophys Acta 1991;1088:197-207.: Isolation and characterization of a human cDNA encoding uracil-DNA glycosylase. PUBMED:2001396 EPMC:2001396


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR006671

Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [PUBMED:12910258], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.

Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [PUBMED:11056549].

Cyclins contain two domains of similar all-alpha fold, of which this entry is associated with the N-terminal domain.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Cyclin (CL0065), which has the following description:

This Clan contains cyclins, Transcription factor IIB (TFIIB), and the Retinoblastoma tumour suppressor proteins. These were predicted to be related by sequence [1].

The clan contains the following 7 members:

CDK5_activator Cyclin Cyclin_C Cyclin_N RB_A RB_B TFIIB

Alignments

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(127)
Full
(6213)
Representative proteomes NCBI
(6602)
Meta
(83)
RP15
(1218)
RP35
(1928)
RP55
(2867)
RP75
(3707)
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  Seed
(127)
Full
(6213)
Representative proteomes NCBI
(6602)
Meta
(83)
RP15
(1218)
RP35
(1928)
RP55
(2867)
RP75
(3707)
Alignment:
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  Seed
(127)
Full
(6213)
Representative proteomes NCBI
(6602)
Meta
(83)
RP15
(1218)
RP35
(1928)
RP55
(2867)
RP75
(3707)
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External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: cyclin;
Type: Domain
Author: Bateman A, Sonnhammer ELL, Griffiths-Jones SR
Number in seed: 127
Number in full: 6213
Average length of the domain: 123.90 aa
Average identity of full alignment: 20 %
Average coverage of the sequence by the domain: 31.34 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.5 20.5
Trusted cut-off 20.5 20.5
Noise cut-off 20.4 20.4
Model length: 127
Family (HMM) version: 18
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Species distribution

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Interactions

There are 6 interactions for this family. More...

CDI K-cyclin_vir_C Cyclin_N Herp-Cyclin Cyclin_C Pkinase

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Cyclin_N domain has been found. There are 190 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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