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 canonical form of the CDK phosphorylation sites has a Proline at +1 and a basic residue at +3 after 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). The basic residue at the P+3 position contacts the phosphothreonine in the activation loop of the CDK (2CCI).
Pattern: ...([ST])P.[KR]
Pattern Probability: 0.0019287
Present in taxon: Eukaryota
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 24 Instances for MOD_CDK_SPxK_1
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 2 selected references:

o 4 GO-Terms:

o 24 Instances for MOD_CDK_SPxK_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q99741 CDC6
71 77 CNTPHLPPCSPPKQGKKENG TP 2 Homo sapiens (Human)
322 328 IRSPYIDGCSPIKNWSPMRL TP 5 Homo sapiens (Human)
P06400 RB1
808 814 GNIYISPLKSPYKISEGLPT TP 6 Homo sapiens (Human)
P06400 RB1
370 376 EEVNVIPPHTPVRTVMNTIQ TP 6 Homo sapiens (Human)
P06400 RB1
249 255 VIPINGSPRTPRRGQNRSAR TP 6 Homo sapiens (Human)
Q13416 ORC2
113 119 AKLASELAKTPQKSVSFSLK TP 7 Homo sapiens (Human)
Q12959 DLG1
440 446 SSFLGQTPASPARYSPVSKA TP 8 Homo sapiens (Human)
Q12959 DLG1
155 161 HGFVSHSHISPIKPTEAVLP TP 8 Homo sapiens (Human)
Q13950-2 RUNX2
448 454 FPMVPGGDRSPSRMLPPCTT TP 5 Homo sapiens (Human)
Q07820 MCL1
89 95 GAEVPDVTATPARLLFFAPT TP 6 Homo sapiens (Human)
Q16665 HIF1A
665 671 YRDTQSRTASPNRAGKGVIE TP 5 Homo sapiens (Human)
369 375 HQHQHSCCESPTRLAQQSHM TP 5 Homo sapiens (Human)
P25054 APC
1357 1363 AVEFSSGAKSPSKSGAQTPK TP 4 Homo sapiens (Human)
P49919 Cdkn1c
339 345 SPNVAPGVGAVEQTPRKRLR TP 2 Mus musculus (House mouse)
P49918 CDKN1C
307 313 SPSAAPGVGSVEQTPRKRLR TP 2 Homo sapiens (Human)
793 799 DGPYSTFLTSSPIRSRSPPA TP 2 Homo sapiens (Human)
Q14814 MEF2D
441 447 HISIKSEPVSPSRERSPAPP TP 2 Homo sapiens (Human)
Q02078 MEF2A
405 411 NISIKSEPISPPRDRMTPSG TP 3 Homo sapiens (Human)
P46527 CDKN1B
184 190 SPNAGSVEQTPKKPGLRRRQ TP 2 Homo sapiens (Human)
P09119 CDC6
369 375 AQVPLTPTTSPVKKSYPEPQ TP 2 Saccharomyces cerevisiae (Baker"s yeast)
P09119 CDC6
40 46 QFTDVTPESSPEKLQFGSQS TP 2 Saccharomyces cerevisiae (Baker"s yeast)
P29366 BEM1
69 75 NRHNSKDITSPEKVIKAKYS TP 1 Saccharomyces cerevisiae (Baker"s yeast)
P29366 BEM1
48 54 PVRYLSSSSTPVKSQRDSSP TP 1 Saccharomyces cerevisiae (Baker"s yeast)
P12931 SRC
72 78 GFNSSDTVTSPQRAGPLAGG TP 1 Homo sapiens (Human)
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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