The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
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 is available 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)
o See 25 Instances for MOD_CDK_SPxxK_3
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 25 Instances for MOD_CDK_SPxxK_3
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q14790 CASP8
CASP8_HUMAN
384 391 QPYLEMDLSSPQTRYIPDEA TP 6 Homo sapiens (Human)
1 
O00418 EEF2K
EF2K_HUMAN
356 363 LRGTEEKCGSPQVRTLSGSR TP 5 Homo sapiens (Human)
1 
Q62095 Ddx3y
DDX3Y_MOUSE
200 207 IELTRYTRPTPVQKHAIPII TP 3 Mus musculus (House mouse)
1 
P30304 CDC25A
MPIP1_HUMAN
113 120 SLPQKLLGCSPALKRSHSDS TP 5 Homo sapiens (Human)
1 
Q13416 ORC2
ORC2_HUMAN
223 230 VVSAPVGKETPSKRMKRDKT TP 7 Homo sapiens (Human)
1 
Q8WWK9 CKAP2
CKAP2_HUMAN
620 627 SAFKELKFLTPVRRSRRLQE TP 8 Homo sapiens (Human)
1 
P04637 TP53
P53_HUMAN
312 319 RALPNNTSSSPQPKKKPLDG TP 4 Homo sapiens (Human)
1 
Q15078 CDK5R1
CD5R1_HUMAN
5 12 MGTVLSLSPSYRKATLFEDG TP 3 Homo sapiens (Human)
1 
P49768 PSEN1
PSN1_HUMAN
351 358 DSHLGPHRSTPESRAAVQEL TP 5 Homo sapiens (Human)
1 
O43464 HTRA2
HTRA2_HUMAN
397 404 VLIHKVILGSPAHRAGLRPG TP 5 Homo sapiens (Human)
1 
Q9BSJ8 ESYT1
ESYT1_HUMAN
321 328 DLQDVAQLRSPLPRGIIRIH TP 3 Homo sapiens (Human)
1 
Q06481 APLP2
APLP2_HUMAN
733 740 GIVEVDPMLTPEERHLNKMQ TP 4 Homo sapiens (Human)
1 
O70589 Cask
CSKP_MOUSE
392 399 LYDKINTKSSPQIRNPPSDA TP 6 Mus musculus (House mouse)
1 
P08592-2 App
A4_RAT
665 672 GVVEVDAAVTPEERHLSKMQ TP 4 Rattus norvegicus (Norway rat)
1 
P28352 Apex1
APEX1_MOUSE
229 236 KGNKKNAGFTPQERQGFGEL TP 5 Mus musculus (House mouse)
1 
P25976 Ubtf
UBF1_MOUSE
386 393 LNINKKQTTSPASKKPSQEG TP 5 Mus musculus (House mouse)
1 
Q9GZV5 WWTR1
WWTR1_HUMAN
282 289 QAAVNPPTMTPDMRSITNNS TP 6 Homo sapiens (Human)
1 
Q9Y6Q9 NCOA3
NCOA3_HUMAN
864 871 LDSPVSVGSSPPVKNISAFP TP 3 Homo sapiens (Human)
1 
Q9Y2I6 NINL
NINL_HUMAN
586 593 PKNRHSPSWSPDGRRRQLPG TP 4 Homo sapiens (Human)
1 
Q02053 Uba1
UBA1_MOUSE
1 8 MSSSPLSKKRRVSGPDPKPG TP 6 Mus musculus (House mouse)
1 
Q0VD86 INCA1
INCA1_HUMAN
20 27 AKCSRVVSRSPPPRLPSQSL TP 3 Homo sapiens (Human)
1 
P39689 Cdkn1a
CDN1A_MOUSE
75 82 SLGLPKVYLSPGSRSRDDLG TP 3 Mus musculus (House mouse)
1 
P50750 CDK9
CDK9_HUMAN
87 94 LIEICRTKASPYNRCKGSIY TP 4 Homo sapiens (Human)
1 
Q15554 TERF2
TERF2_HUMAN
362 369 VLPTQALPASPALKNKRPRK TP 2 Homo sapiens (Human)
2 
P10085 Myod1
MYOD1_MOUSE
2 9 MELLSPPLRDIDLTGPDGSL TP 4 Mus musculus (House mouse)
1 
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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