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Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved
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, respon ...
that functions as a serine/threonine protein kinase, and is a key player in
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 ...
regulation. It has been highly studied in the budding yeast '' S. cerevisiae'', and the fission yeast '' S. pombe'', where it is encoded by
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s ''cdc28'' an
''cdc2''
respectively. With its
cyclin Cyclin is a family of proteins that controls the progression of a cell through the cell cycle by activating cyclin-dependent kinase (CDK) enzymes or group of enzymes required for synthesis of cell cycle. Etymology Cyclins were originally disco ...
partners, Cdk1 forms complexes that
phosphorylate In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...
a variety of target substrates (over 75 have been identified in budding yeast); phosphorylation of these proteins leads to cell cycle progression.


Structure

Cdk1 is a small protein (approximately 34 kilodaltons), and is highly conserved. The human homolog of Cdk1, ''CDK1'', shares approximately 63% amino-acid identity with its yeast homolog. Furthermore, human ''CDK1'' is capable of rescuing fission yeast carrying a ''cdc2'' mutation. Cdk1 is comprised mostly by the bare protein kinase motif, which other protein kinases share. Cdk1, like other kinases, contains a cleft in which
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
fits. Substrates of Cdk1 bind near the mouth of the cleft, and Cdk1 residues catalyze the covalent bonding of the γ-phosphate to the oxygen of the
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
serine/threonine of the substrate. In addition to this catalytic core, Cdk1, like other cyclin-dependent kinases, contains a T-loop, which, in the absence of an interacting cyclin, prevents substrate binding to the Cdk1 active site. Cdk1 also contains a PSTAIRE helix, which, upon cyclin binding, moves and rearranges the active site, facilitating Cdk1 kinase activities.


Function

When bound to its cyclin partners, Cdk1 phosphorylation leads to cell cycle progression. Cdk1 activity is best understood in ''S. cerevisiae'', so Cdk1 ''S. cerevisiae'' activity is described here. In the budding yeast, initial cell cycle entry is controlled by two regulatory complexes, SBF (SCB-binding factor) and MBF (MCB-binding factor). These two complexes control G1/S gene transcription; however, they are normally inactive. SBF is inhibited by the protein Whi5; however, when phosphorylated by Cln3-Cdk1, Whi5 is ejected from the nucleus, allowing for transcription of the G1/S
regulon In molecular genetics, a regulon is a group of genes that are regulated as a unit, generally controlled by the same regulatory gene that expresses a protein acting as a repressor or activator. This terminology is generally, although not exclusive ...
, which includes the G1/S cyclins Cln1,2. G1/S cyclin-Cdk1 activity leads to preparation for S phase entry (e.g., duplication of centromeres or the spindle pole body), and a rise in the S cyclins (Clb5,6 in ''S. cerevisiae''). Clb5,6-Cdk1 complexes directly lead to replication origin initiation; however, they are inhibited by Sic1, preventing premature S phase initiation. Cln1,2 and/or Clb5,6-Cdk1 complex activity leads to a sudden drop in Sic1 levels, allowing for coherent S phase entry. Finally, phosphorylation by M cyclins (e.g., Clb1, 2, 3 and 4) in complex with Cdk1 leads to spindle assembly and sister chromatid alignment. Cdk1 phosphorylation also leads to the activation of the ubiquitin-protein ligase APCCdc20, an activation which allows for chromatid segregation and, furthermore, degradation of M-phase cyclins. This destruction of M cyclins leads to the final events of mitosis (e.g., spindle disassembly, mitotic exit).


Regulation

Given its essential role in cell cycle progression, Cdk1 is highly regulated. Most obviously, Cdk1 is regulated by its binding with its cyclin partners. Cyclin binding alters access to the active site of Cdk1, allowing for Cdk1 activity; furthermore, cyclins impart specificity to Cdk1 activity. At least some cyclins contain a hydrophobic patch which may directly interact with substrates, conferring target specificity. Furthermore, cyclins can target Cdk1 to particular subcellular locations. In addition to regulation by cyclins, Cdk1 is regulated by phosphorylation. A conserved tyrosine (Tyr15 in humans) leads to inhibition of Cdk1; this phosphorylation is thought to alter ATP orientation, preventing efficient kinase activity. In S. pombe, for example, incomplete DNA synthesis may lead to stabilization of this phosphorylation, preventing mitotic progression.
Wee1 Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast ''Schizosaccharomyces pombe'' (''S. pombe'')Wee1has a molecular mass of 96  kDa and is a key regulator of cell cycle progression. It influence ...
, conserved among all eukaryotes phosphorylates Tyr15, whereas members of the Cdc25 family are phosphatases, counteracting this activity. The balance between the two is thought to help govern cell cycle progression.
Wee1 Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast ''Schizosaccharomyces pombe'' (''S. pombe'')Wee1has a molecular mass of 96  kDa and is a key regulator of cell cycle progression. It influence ...
is controlled upstream by Cdr1, Cdr2, and Pom1. Cdk1-cyclin complexes are also governed by direct binding of Cdk inhibitor proteins (CKIs). One such protein, already discussed, is Sic1. Sic1 is a stoichiometric inhibitor that binds directly to Clb5,6-Cdk1 complexes. Multisite phosphorylation, by Cdk1-Cln1/2, of Sic1 is thought to time Sic1 ubiquitination and destruction, and by extension, the timing of S-phase entry. Only until Sic1 inhibition is overcome can Clb5,6 activity occur and S phase initiation may begin.


Interactions

Cdk1 has been shown to interact with: *
BCL2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death ( apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosi ...
, * CCNB1, * CCNE1, * CDKN3 * DAB2, * FANCC, * GADD45A, * LATS1, *
LYN Ubisoft Montpellier is a French video game developer and a studio of Ubisoft based in Castelnau-le-Lez. Founded in 1994 as Ubi Pictures, it is best known for developing the ''Rayman'' and ''Beyond Good & Evil'' series. At 350 employees as of Se ...
, * P53, and * UBC.


See also

* E2F#E2F.2FpRb complexes * Hyperphosphorylation * cdc25 * Maturation promoting factor * CDK *
cyclin A Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cel ...
* cyclin B *
cyclin D Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 (in zebra mus ...
*
cyclin E Cyclin E is a member of the cyclin family. Cyclin E binds to G1 phase, G1 phase Cdk2, which is required for the transition from G1 to S phase of the cell cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphoryla ...
* Wee (cell cycle) Mastl


References


Further reading

* * * * * * * * * * * * * * * * * * * *


External links

* {{DEFAULTSORT:Cyclin-dependent kinase 01 Cell cycle Proteins EC 2.7.11 Cell cycle regulators de:Cyclin-abhängige Kinase 1#Die Entdeckung des cdc2-Gens