| Structural highlights
4krc is a 2 chain structure with sequence from Baker's yeast. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 4krd |
| Gene: | P7102.18A, PHO85, SSG3, YPL031C (Baker's yeast), G2838, PCL10, YGL134W (Baker's yeast) |
| Activity: | Cyclin-dependent kinase, with EC number 2.7.11.22 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[PHO85_YEAST] Cyclin-dependent protein kinase (CDK) catalytic subunit that regulates multiple cell cycle and metabolic processes in response to nutrient availability. Associates with different cyclins, that control kinase activity, substrate-specificity and subcellular location of the kinase. Favorable growth conditions always result in activated cyclin-CDK complexes. Regulates metabolic processes when associated with PHO80 cyclin family members (PH080, PCL6, PCL7, PCL8 and PCL10), and cell cycle and morphogenesis processes when associated with PCL1,2 cyclin family members (PCL1, PCL2, CLG1, PCL5 and PCL9). When associated with PHO80, negatively regulates the expression of phosphate-starvation-responsive genes under phosphate-rich conditions. The PHO80-PHO85 cyclin-CDK holoenzyme phosphorylates and inactivates the transcription factor PHO4 by promoting its export to the cytoplasm. PHO80-PHO85 phosphorylates and inactivates protein kinase RIM15 by retaining it in the cytoplasm, antagonizing RIM15-induced entry into stationary phase. PHO80-PHO85 also phosphorylates and inactivates the calcineurin-responsive transcription factor CRZ1, linking cyclin-CDK activity to calcium signaling. Together with the cyclins PCL6/PCL7 and PCL8/PCL10, negatively controls glycogen accumulation. When associated with cyclins PCL6 and PCL7, controls glycogen phosphorylase and glycogen synthase activities. PCL6-PHO85 and PCL7-PHO85 phosphorylate and inactivate the phosphatase PP1-2 inhibitor GLC8, causing activation of PP1-2, which then dephosphorylates and activates glycogen phosphorylase. When associated with cyclins PCL8 and PCL10, has glycogen synthase kinase activity. PCL10-PHO85 phosphorylates and negatively regulates glycogen synthase GSY2. Association with PCL1 and PCL2 is required for cell cycle progression at start in the absence of the CDC28-dependent G1 cyclins CLN1 and CLN2. PCL1-PHO85 is involved in phosphorylation of the CDK inhibitor (CKI) SIC1, which is required for its ubiquitination and degradation, releasing repression of b-type cyclins and promoting exit from mitosis. When associated with cyclins PCL1 and PCL2, positively controls degradation of sphingoid long chain base kinase LCB4 via phosphorylation of LCB4, which is required for its ubiquitination and degradation. PCL1-PHO85 also phosphorylates HMS1, NCP1 and NPA3, which may all have a role in mitotic exit. PCL2-PHO85 also phosphorylates RVS167, linking cyclin-CDK activity with organization of the actin cytoskeleton. When associated with PCL5, positively controls degradation of transcription factor GCN4 via phosphorylation of GCN4, which is required for its degradation by the E3 ubiquitin ligase complex SCF(Cdc4). When associated with PCL9, may have a role in bud site selection in G1 phase. PHO85 also phosphorylates the transcription factor SWI5.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [PCL10_YEAST] Cyclin partner of the cyclin-dependent kinase (CDK) PHO85. Together with cyclin PCL8, negatively controls glycogen accumulation under favorable growth conditions. The PCL10-PHO85 cyclin-CDK holoenzyme has glycogen synthase kinase activity and phosphorylates and negatively regulates glycogen synthase GSY2. Also has minor GLC8 kinase activity.[23] [24] [25]
Publication Abstract from PubMed
Pho85 is a versatile cyclin dependent kinase (CDK) found in budding yeast that regulates a myriad of eukaryotic cellular functions in concert with ten cyclins (called Pcls). Unlike cell cycle CDKs which require phosphorylation of a serine/threonine residue by a CDK-activating kinase (CAK) for full activation, Pho85 require no phosphorylation despite the presence of an equivalent residue. The Pho85-Pcl10 complex is a key regulator of glycogen metabolism by phosphorylating the substrate Gsy2, the predominant, nutritionally regulated form of glycogen synthase. Here we report the crystal structures of Pho85-Pcl10 and its complex with the ATP analog, ATP-gammaS. The structure solidified the mechanism for by-passing CDK phosphorylation to achieve full catalytic activity. An aspartate residue, invariant in all Pcls, acts as a surrogate for the phosphoryl adduct of the phosphorylated, fully activated CDK2, the prototypic cell cycle CDK, complexed with cyclin A. Unlike the canonical recognition motif, SPXK/R, of phosphorylation sites of substrates of several cell cycle CDKs, the motif in the Gys2 substrate of Pho85-Pcl10 is SPXX. CDK5, an important signal transducer in neural development and the closest known functional homolog of Pho85, does not require phosphorylation either, and we found that in its crystal structure complexed with p25 cyclin a water/hydroxide molecule remarkably plays a similar role to the phosphoryl or aspartate group. Comparison between Pho85-Pcl10, phosphorylated CDK2-cyclin A and CDK5-p25 complexes reveals the convergent structural characteristics necessary for full kinase activity and the variations in the substrate recognition mechanism.
New Structural Insights into Phosphorylation-free Mechanism for Full CDK-Cyclin Activity and Substrate Recognition.,Zheng F, Quiocho FA J Biol Chem. 2013 Sep 10. PMID:24022486[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Toh-e A, Tanaka K, Uesono Y, Wickner RB. PHO85, a negative regulator of the PHO system, is a homolog of the protein kinase gene, CDC28, of Saccharomyces cerevisiae. Mol Gen Genet. 1988 Sep;214(1):162-4. PMID:3067079
- ↑ Kaffman A, Herskowitz I, Tjian R, O'Shea EK. Phosphorylation of the transcription factor PHO4 by a cyclin-CDK complex, PHO80-PHO85. Science. 1994 Feb 25;263(5150):1153-6. PMID:8108735
- ↑ Espinoza FH, Ogas J, Herskowitz I, Morgan DO. Cell cycle control by a complex of the cyclin HCS26 (PCL1) and the kinase PHO85. Science. 1994 Nov 25;266(5189):1388-91. PMID:7973730
- ↑ O'Neill EM, Kaffman A, Jolly ER, O'Shea EK. Regulation of PHO4 nuclear localization by the PHO80-PHO85 cyclin-CDK complex. Science. 1996 Jan 12;271(5246):209-12. PMID:8539622
- ↑ Lee J, Colwill K, Aneliunas V, Tennyson C, Moore L, Ho Y, Andrews B. Interaction of yeast Rvs167 and Pho85 cyclin-dependent kinase complexes may link the cell cycle to the actin cytoskeleton. Curr Biol. 1998 Dec 3;8(24):1310-21. PMID:9843683
- ↑ Nishizawa M, Kawasumi M, Fujino M, Toh-e A. Phosphorylation of sic1, a cyclin-dependent kinase (Cdk) inhibitor, by Cdk including Pho85 kinase is required for its prompt degradation. Mol Biol Cell. 1998 Sep;9(9):2393-405. PMID:9725902
- ↑ Huang D, Moffat J, Wilson WA, Moore L, Cheng C, Roach PJ, Andrews B. Cyclin partners determine Pho85 protein kinase substrate specificity in vitro and in vivo: control of glycogen biosynthesis by Pcl8 and Pcl10. Mol Cell Biol. 1998 Jun;18(6):3289-99. PMID:9584169
- ↑ Tennyson CN, Lee J, Andrews BJ. A role for the Pcl9-Pho85 cyclin-cdk complex at the M/G1 boundary in Saccharomyces cerevisiae. Mol Microbiol. 1998 Apr;28(1):69-79. PMID:9593297
- ↑ Wilson WA, Mahrenholz AM, Roach PJ. Substrate targeting of the yeast cyclin-dependent kinase Pho85p by the cyclin Pcl10p. Mol Cell Biol. 1999 Oct;19(10):7020-30. PMID:10490639
- ↑ Measday V, McBride H, Moffat J, Stillman D, Andrews B. Interactions between Pho85 cyclin-dependent kinase complexes and the Swi5 transcription factor in budding yeast. Mol Microbiol. 2000 Feb;35(4):825-34. PMID:10692159
- ↑ Wang Z, Wilson WA, Fujino MA, Roach PJ. The yeast cyclins Pc16p and Pc17p are involved in the control of glycogen storage by the cyclin-dependent protein kinase Pho85p. FEBS Lett. 2001 Oct 12;506(3):277-80. PMID:11602261
- ↑ Shi XZ, Ao SZ. [Phosphorylation of YLR190w by PAP1 PHO85 kinase complex] Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002, Mar;34(2):187-92. PMID:12006994
- ↑ Shi XZ, Ao SZ. Analysis of phosphorylation of YJL084c, a yeast protein. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002, Jul;34(4):433-8. PMID:12098764
- ↑ Shemer R, Meimoun A, Holtzman T, Kornitzer D. Regulation of the transcription factor Gcn4 by Pho85 cyclin PCL5. Mol Cell Biol. 2002 Aug;22(15):5395-404. PMID:12101234
- ↑ Tan YS, Morcos PA, Cannon JF. Pho85 phosphorylates the Glc7 protein phosphatase regulator Glc8 in vivo. J Biol Chem. 2003 Jan 3;278(1):147-53. Epub 2002 Oct 28. PMID:12407105 doi:10.1074/jbc.M208058200
- ↑ Friesen H, Murphy K, Breitkreutz A, Tyers M, Andrews B. Regulation of the yeast amphiphysin homologue Rvs167p by phosphorylation. Mol Biol Cell. 2003 Jul;14(7):3027-40. Epub 2003 Apr 4. PMID:12857883 doi:10.1091/mbc.E02-09-0613
- ↑ Waters NC, Knight JP, Creasy CL, Bergman LW. The yeast Pho80-Pho85 cyclin-CDK complex has multiple substrates. Curr Genet. 2004 Jul;46(1):1-9. Epub 2004 Apr 1. PMID:15057567 doi:10.1007/s00294-004-0501-0
- ↑ Keniry ME, Kemp HA, Rivers DM, Sprague GF Jr. The identification of Pcl1-interacting proteins that genetically interact with Cla4 may indicate a link between G1 progression and mitotic exit. Genetics. 2004 Mar;166(3):1177-86. PMID:15082539
- ↑ Wilson WA, Wang Z, Roach PJ. Regulation of yeast glycogen phosphorylase by the cyclin-dependent protein kinase Pho85p. Biochem Biophys Res Commun. 2005 Apr 1;329(1):161-7. PMID:15721288 doi:S0006-291X(05)00168-3
- ↑ Wanke V, Pedruzzi I, Cameroni E, Dubouloz F, De Virgilio C. Regulation of G0 entry by the Pho80-Pho85 cyclin-CDK complex. EMBO J. 2005 Dec 21;24(24):4271-8. Epub 2005 Nov 24. PMID:16308562 doi:7600889
- ↑ Iwaki S, Kihara A, Sano T, Igarashi Y. Phosphorylation by Pho85 cyclin-dependent kinase acts as a signal for the down-regulation of the yeast sphingoid long-chain base kinase Lcb4 during the stationary phase. J Biol Chem. 2005 Feb 25;280(8):6520-7. Epub 2004 Dec 14. PMID:15598647 doi:M410908200
- ↑ Sopko R, Huang D, Preston N, Chua G, Papp B, Kafadar K, Snyder M, Oliver SG, Cyert M, Hughes TR, Boone C, Andrews B. Mapping pathways and phenotypes by systematic gene overexpression. Mol Cell. 2006 Feb 3;21(3):319-30. PMID:16455487 doi:10.1016/j.molcel.2005.12.011
- ↑ Huang D, Moffat J, Wilson WA, Moore L, Cheng C, Roach PJ, Andrews B. Cyclin partners determine Pho85 protein kinase substrate specificity in vitro and in vivo: control of glycogen biosynthesis by Pcl8 and Pcl10. Mol Cell Biol. 1998 Jun;18(6):3289-99. PMID:9584169
- ↑ Wilson WA, Mahrenholz AM, Roach PJ. Substrate targeting of the yeast cyclin-dependent kinase Pho85p by the cyclin Pcl10p. Mol Cell Biol. 1999 Oct;19(10):7020-30. PMID:10490639
- ↑ Tan YS, Morcos PA, Cannon JF. Pho85 phosphorylates the Glc7 protein phosphatase regulator Glc8 in vivo. J Biol Chem. 2003 Jan 3;278(1):147-53. Epub 2002 Oct 28. PMID:12407105 doi:10.1074/jbc.M208058200
- ↑ Zheng F, Quiocho FA. New Structural Insights into Phosphorylation-free Mechanism for Full CDK-Cyclin Activity and Substrate Recognition. J Biol Chem. 2013 Sep 10. PMID:24022486 doi:10.1074/jbc.M113.502773
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