The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
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 short form of the CDK phosphorylation site has a Proline at +1 and a basic residue at +2 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 short CDK substrate peptide. In the CDK2 complex which has positive residues at both the +2 and +3 positions, the +2 position is an arginine, contacting the tri-phosphate group of the bound ATP (2CCI).

Pattern: ...([ST])P[RK]
Pattern Probability: 0.0019287
Present in taxon: Eukaryota
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 18 Instances for MOD_CDK_SPK_2
o 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).
o 9 selected references:

o 21 GO-Terms:

o 18 Instances for MOD_CDK_SPK_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q15398 DLGAP5
636 641 SSEGPSQRLGTPKSVNKAVS TP 7 Homo sapiens (Human)
Q53EZ4 CEP55
422 427 ETENREKVAASPKSPTAALN TP 6 Homo sapiens (Human)
P06400 RB1
249 254 AVIPINGSPRTPRRGQNRSA TP 6 Homo sapiens (Human)
Q62799 Erbb3
1117 1122 SVCRSRSRSRSPRPRGDSAY TP 6 Rattus norvegicus (Norway rat)
P15311 EZR
232 237 LNIYEKDDKLTPKIGFPWSE TP 4 Homo sapiens (Human)
474 479 SPPADALKLRSPRGSPDGSL TP 7 Homo sapiens (Human)
Q9ESJ1 Cables1
271 276 PLRRCRTLSGSPRPKNFKKI TP 6 Mus musculus (House mouse)
P19103 Ppp1r1a
64 69 NPLLKSTLSMSPRQRKKMTR TP 7 Rattus norvegicus (Norway rat)
O00443 PIK3C2A
256 261 TDSKVSNLQVSPKSEDISKF TP 7 Homo sapiens (Human)
P99024 Tubb5
169 174 RIMNTFSVVPSPKVSDTVVE TP 5 Mus musculus (House mouse)
P06748 NPM1
234 239 SFKKQEKTPKTPKGPSSVED TP 5 Homo sapiens (Human)
P06748 NPM1
216 221 QNGKDSKPSSTPRSKGQESF TP 5 Homo sapiens (Human)
P10085 Myod1
197 202 EHYSGDSDASSPRSNCSDGM TP 5 Mus musculus (House mouse)
P26358 DNMT1
151 156 DGEAKPEPSPSPRITRKSTR TP 7 Homo sapiens (Human)
P25206 Mcm3
109 114 LEGSFGSKHVSPRTLTSCFL TP 5 Mus musculus (House mouse)
P55211 CASP9
122 127 IRKPEVLRPETPRPVDIGSG TP 4 Homo sapiens (Human)
P10275 AR
80 85 QQQQQQQQETSPRQQQQQQG TP 3 Homo sapiens (Human)
Q15398 DLGAP5
326 331 GLKTYQVTPMTPRSANAFLT TP 7 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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