Accession: | |
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Functional site class: | CDK Phosphorylation Site |
Functional site description: | Cyclin-dependent kinases (CDKs) and their associated regulatory cyclins are central for timely regulation of cell-cycle progression. From yeast to human cell cycle progression and cell division require the activation of CDKs. Cyclins activate CDKs which are important for ensuring that CDKs are functional at the correct points in the cell cycle, targeted to their substrates and localized to the correct subcellular locations. CDKs are proline-directed serine/threonine kinases which have some specificity at [ST]P?[KR] site for phosphorylation. CDK-mediated phosphorylation regulates many biological processes like DNA replication, mitotic progression, nuclear envelope breakdown, chromosome condensation, spindle assembly, and the degradation of cyclins. Since CDKs have been found deregulated in many human cancers, they are considered as interesting therapeutics targets. |
ELMs with same func. site: | MOD_CDK_SPK_2 MOD_CDK_SPxK_1 MOD_CDK_SPxxK_3 |
ELM Description: | The long form of the CDK phosphorylation site has a Proline at +1 and a basic residue at +4 following the phosphorylatable Ser/Thr position. The motif binds in an extended conformation across the catalytic site on the surface of the kinase, in the CDK2 structure, contacting only the C-terminal lobe of CDK2, especially the activation segment (Brown,2001). The presence of the Pro residue next to the phosphorylatable Ser/Thr is important. In proline-directed kinases like CDK, the carbonyl group of their so-called toggle residue (V164) is oriented away from the catalytic cleft creating a hydrophobic pocket. As the proline is the only residue to fit this pocket, it is strongly favoured at the P+1 position. Binding of any substrate that does not have a Pro at the P+1 position is unfavourable because of an unsatisfied hydrogen bond from the nitrogen atom in the main chain of the substrate (Zhu,2005). No structure is available for a long CDK substrate peptide but it is likely that, as with the +3 residue, a positively charged +4 residue can contact the phosphothreonine in the activation loop of the CDK (2CCI). |
Pattern: | ...([ST])P..[RK] |
Pattern Probability: | 0.0019287 |
Present in taxon: | Eukaryota |
Interaction Domain: |
Pkinase (PF00069)
Protein kinase domain
(Stochiometry: 1 : 1)
|
Abstract |
Protein phosphorylation is a key regulatory mechanism for cell cycle regulation in eukaryotes. Progression of cells through the cell cycle is tightly regulated by cyclin-CDK dimeric kinase complexes where CDK is the catalytic kinase subunit and cyclin is the activating subunit. In higher organisms different CDKs associate with one or more different cyclins at specific phase of cell cycle. Of the 20 CDKs identified, CDK1-11 are the best characterized. CDK1, 2, 3, 4 and 6 are key players with major regulatory roles in core cell cycle at different phases like G1/S (CDK3, 4, 6), S (CDK2) and G2/M (CDK1). CDK5 functions primarily in neuronal development and CDK 7,8,9,10,11 function mainly as transcriptional regulators. Most CDKs and their associated cyclins have tightly controlled cell phase-specific expression. Cyclin D functions during G1/S, cyclin E at S phase and cyclin A/B classes at G2/M (Malumbres,2009). CDKs are proline-directed serine/threonine-protein kinases with classically a preference for the [ST]P.KR] sequence as a consequence of the presence of a hydrophobic pocket near the catalytic site that accommodates the proline (position +1) (Brown,2001) and negative charge to bind the Lys/Arg. However, the requirement for the basic residue in the +3 position is not strictly maintained in all CDKs. Some display a preference for a short [ST]P[RK] consensus site (Lees,1992) while others show preference for a long CDK phosphorylation site ([ST]P..[KR]) (Hodeify,2011). There are also even longer SP…[KR] reports (not yet annotated in ELM) (Esashi,2005). There are in addition some reports of CDK phosphorylation sites which require only an SP motif and others even suggesting non-SP sites (25604483). CDKs can be specific to particular substrates but also at the same time they may have overlapping substrate specificity: Partly this may be done to differences in spatio-temporal regulation. Also different CDKs can phosphorylate the same substrate on different sites to effect different substrate functions. So the identification of substrates of specific CDK-Cyclin complexes is important as both the substrate specificity and availability are necessary to ensure that the right cellular events are understood to occur in the right order. Since CDKs have been found deregulated in many human cancers, they are considered as interesting therapeutics targets in cancer. For example the inhibitor of CDK4/6 has been tested in Phase 3 clinical trials e.g. PALOMA-3 (26947331). |
21 GO-Terms:
25 Instances for MOD_CDK_SPxxK_3
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Please cite:
The Eukaryotic Linear Motif resource: 2022 release.
(PMID:34718738)
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement