| Structural highlights
Disease
PLK1_HUMAN Note=Defects in PLK1 are associated with some cancers, such as gastric, thyroid or B-cell lymphomas. Expression is cancer increased in tumor tissues with a poor prognosis, suggesting a role in malignant transformations and carcinogenesis.
Function
PLK1_HUMAN Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, MLF1IP, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, PLK1S1/KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGOL1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1 and WEE1. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating PLK1S1/KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, MLF1IP, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, MLF1IP, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGOL1: required for spindle pole localization of isoform 3 of SGOL1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]
Publication Abstract from PubMed
Targeting protein - protein interactions (PPIs) has emerged as an important area of discovery for anticancer therapeutic development. In the case of phospho-dependent PPIs, such as the polo-like kinase 1 (Plk1) polo-box domain (PBD), a phosphorylated protein residue can provide high-affinity recognition and binding to target protein hot spots. Developing antagonists of the Plk1 PBD can be particularly challenging if one relies solely on interactions within and proximal to the phospho-binding pocket. Fortunately, the affinity of phospho-dependent PPI antagonists can be significantly enhanced by taking advantage of interactions in both the phospho-binding site and hidden "cryptic" pockets that may be revealed on ligand binding. In our current paper, we describe the design and synthesis of macrocyclic peptide mimetics directed against the Plk1 PBD, which are characterized by a new glutamic acid analog that simultaneously serves as a ring-closing junction that provides accesses to a cryptic binding pocket, while at the same time achieving proper orientation of a phosphothreonine (pT) residue for optimal interaction in the signature phospho-binding pocket. Macrocycles prepared with this new amino acid analog introduce additional hydrogen-bonding interactions not found in the open-chain linear parent peptide. It is noteworthy that this new glutamic acid-based amino acid analog represents the first example of extremely high affinity ligands where access to the cryptic pocket from the pT-2 position is made possible with a residue that is not based on histidine. The concepts employed in the design and synthesis of these new macrocyclic peptide mimetics should be useful for further studies directed against the Plk1 PBD and potentially for ligands directed against other PPI targets.
Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain - binding peptide macrocycles.,Hymel D, Tsuji K, Grant RA, Chingle RM, Kunciw DL, Yaffe MB, Burke TR Jr Org Biomol Chem. 2021 Sep 22;19(36):7843-7854. doi: 10.1039/d1ob01120k. PMID:34346472[34]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lane HA, Nigg EA. Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J Cell Biol. 1996 Dec;135(6 Pt 2):1701-13. PMID:8991084
- ↑ Roshak AK, Capper EA, Imburgia C, Fornwald J, Scott G, Marshall LA. The human polo-like kinase, PLK, regulates cdc2/cyclin B through phosphorylation and activation of the cdc25C phosphatase. Cell Signal. 2000 Jun;12(6):405-11. PMID:11202906
- ↑ Jang YJ, Ma S, Terada Y, Erikson RL. Phosphorylation of threonine 210 and the role of serine 137 in the regulation of mammalian polo-like kinase. J Biol Chem. 2002 Nov 15;277(46):44115-20. Epub 2002 Aug 30. PMID:12207013 doi:10.1074/jbc.M202172200
- ↑ Yuan J, Eckerdt F, Bereiter-Hahn J, Kurunci-Csacsko E, Kaufmann M, Strebhardt K. Cooperative phosphorylation including the activity of polo-like kinase 1 regulates the subcellular localization of cyclin B1. Oncogene. 2002 Nov 28;21(54):8282-92. PMID:12447691 doi:10.1038/sj.onc.1206011
- ↑ Casenghi M, Meraldi P, Weinhart U, Duncan PI, Korner R, Nigg EA. Polo-like kinase 1 regulates Nlp, a centrosome protein involved in microtubule nucleation. Dev Cell. 2003 Jul;5(1):113-25. PMID:12852856
- ↑ Nakajima H, Toyoshima-Morimoto F, Taniguchi E, Nishida E. Identification of a consensus motif for Plk (Polo-like kinase) phosphorylation reveals Myt1 as a Plk1 substrate. J Biol Chem. 2003 Jul 11;278(28):25277-80. Epub 2003 May 8. PMID:12738781 doi:10.1074/jbc.C300126200
- ↑ Neef R, Preisinger C, Sutcliffe J, Kopajtich R, Nigg EA, Mayer TU, Barr FA. Phosphorylation of mitotic kinesin-like protein 2 by polo-like kinase 1 is required for cytokinesis. J Cell Biol. 2003 Sep 1;162(5):863-75. Epub 2003 Aug 25. PMID:12939256 doi:http://dx.doi.org/10.1083/jcb.200306009
- ↑ Jackman M, Lindon C, Nigg EA, Pines J. Active cyclin B1-Cdk1 first appears on centrosomes in prophase. Nat Cell Biol. 2003 Feb;5(2):143-8. PMID:12524548 doi:10.1038/ncb918
- ↑ Lindon C, Pines J. Ordered proteolysis in anaphase inactivates Plk1 to contribute to proper mitotic exit in human cells. J Cell Biol. 2004 Jan 19;164(2):233-41. PMID:14734534 doi:10.1083/jcb.200309035
- ↑ Hansen DV, Loktev AV, Ban KH, Jackson PK. Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emi1. Mol Biol Cell. 2004 Dec;15(12):5623-34. Epub 2004 Oct 6. PMID:15469984 doi:10.1091/mbc.E04-07-0598
- ↑ Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, Osada H. M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4419-24. Epub 2004 Mar 22. PMID:15070733 doi:10.1073/pnas.0307700101
- ↑ Moshe Y, Boulaire J, Pagano M, Hershko A. Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proc Natl Acad Sci U S A. 2004 May 25;101(21):7937-42. Epub 2004 May 17. PMID:15148369 doi:10.1073/pnas.0402442101
- ↑ Fabbro M, Zhou BB, Takahashi M, Sarcevic B, Lal P, Graham ME, Gabrielli BG, Robinson PJ, Nigg EA, Ono Y, Khanna KK. Cdk1/Erk2- and Plk1-dependent phosphorylation of a centrosome protein, Cep55, is required for its recruitment to midbody and cytokinesis. Dev Cell. 2005 Oct;9(4):477-88. PMID:16198290 doi:S1534-5807(05)00337-0
- ↑ Oshimori N, Ohsugi M, Yamamoto T. The Plk1 target Kizuna stabilizes mitotic centrosomes to ensure spindle bipolarity. Nat Cell Biol. 2006 Oct;8(10):1095-101. Epub 2006 Sep 17. PMID:16980960 doi:10.1038/ncb1474
- ↑ Niiya F, Tatsumoto T, Lee KS, Miki T. Phosphorylation of the cytokinesis regulator ECT2 at G2/M phase stimulates association of the mitotic kinase Plk1 and accumulation of GTP-bound RhoA. Oncogene. 2006 Feb 9;25(6):827-37. PMID:16247472 doi:10.1038/sj.onc.1209124
- ↑ Kang YH, Park JE, Yu LR, Soung NK, Yun SM, Bang JK, Seong YS, Yu H, Garfield S, Veenstra TD, Lee KS. Self-regulated Plk1 recruitment to kinetochores by the Plk1-PBIP1 interaction is critical for proper chromosome segregation. Mol Cell. 2006 Nov 3;24(3):409-22. PMID:17081991 doi:S1097-2765(06)00705-2
- ↑ Pouwels J, Kukkonen AM, Lan W, Daum JR, Gorbsky GJ, Stukenberg T, Kallio MJ. Shugoshin 1 plays a central role in kinetochore assembly and is required for kinetochore targeting of Plk1. Cell Cycle. 2007 Jul 1;6(13):1579-85. Epub 2007 May 16. PMID:17617734
- ↑ Matsumura S, Toyoshima F, Nishida E. Polo-like kinase 1 facilitates chromosome alignment during prometaphase through BubR1. J Biol Chem. 2007 May 18;282(20):15217-27. Epub 2007 Mar 21. PMID:17376779 doi:10.1074/jbc.M611053200
- ↑ Neef R, Gruneberg U, Kopajtich R, Li X, Nigg EA, Sillje H, Barr FA. Choice of Plk1 docking partners during mitosis and cytokinesis is controlled by the activation state of Cdk1. Nat Cell Biol. 2007 Apr;9(4):436-44. Epub 2007 Mar 11. PMID:17351640 doi:10.1038/ncb1557
- ↑ Soond SM, Barry SP, Melino G, Knight RA, Latchman DS, Stephanou A. p73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. Cell Cycle. 2008 May 1;7(9):1214-23. Epub 2008 Feb 15. PMID:18418051
- ↑ Chan EH, Santamaria A, Sillje HH, Nigg EA. Plk1 regulates mitotic Aurora A function through betaTrCP-dependent degradation of hBora. Chromosoma. 2008 Oct;117(5):457-69. doi: 10.1007/s00412-008-0165-5. Epub 2008 Jun, 3. PMID:18521620 doi:10.1007/s00412-008-0165-5
- ↑ Wang X, Yang Y, Duan Q, Jiang N, Huang Y, Darzynkiewicz Z, Dai W. sSgo1, a major splice variant of Sgo1, functions in centriole cohesion where it is regulated by Plk1. Dev Cell. 2008 Mar;14(3):331-41. doi: 10.1016/j.devcel.2007.12.007. PMID:18331714 doi:10.1016/j.devcel.2007.12.007
- ↑ Yamashiro S, Yamakita Y, Totsukawa G, Goto H, Kaibuchi K, Ito M, Hartshorne DJ, Matsumura F. Myosin phosphatase-targeting subunit 1 regulates mitosis by antagonizing polo-like kinase 1. Dev Cell. 2008 May;14(5):787-97. doi: 10.1016/j.devcel.2008.02.013. PMID:18477460 doi:10.1016/j.devcel.2008.02.013
- ↑ Koida N, Ozaki T, Yamamoto H, Ono S, Koda T, Ando K, Okoshi R, Kamijo T, Omura K, Nakagawara A. Inhibitory role of Plk1 in the regulation of p73-dependent apoptosis through physical interaction and phosphorylation. J Biol Chem. 2008 Mar 28;283(13):8555-63. doi: 10.1074/jbc.M710608200. Epub 2008 , Jan 3. PMID:18174154 doi:10.1074/jbc.M710608200
- ↑ Fu Z, Malureanu L, Huang J, Wang W, Li H, van Deursen JM, Tindall DJ, Chen J. Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression. Nat Cell Biol. 2008 Sep;10(9):1076-82. doi: 10.1038/ncb1767. PMID:19160488 doi:10.1038/ncb1767
- ↑ Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, Clouin C, Taylor SS, Yaffe MB, Medema RH. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature. 2008 Sep 4;455(7209):119-23. doi: 10.1038/nature07185. Epub 2008 Jul 9. PMID:18615013 doi:10.1038/nature07185
- ↑ Yang X, Li H, Zhou Z, Wang WH, Deng A, Andrisani O, Liu X. Plk1-mediated phosphorylation of Topors regulates p53 stability. J Biol Chem. 2009 Jul 10;284(28):18588-92. doi: 10.1074/jbc.C109.001560. Epub, 2009 May 27. PMID:19473992 doi:10.1074/jbc.C109.001560
- ↑ Zhang X, Chen Q, Feng J, Hou J, Yang F, Liu J, Jiang Q, Zhang C. Sequential phosphorylation of Nedd1 by Cdk1 and Plk1 is required for targeting of the gammaTuRC to the centrosome. J Cell Sci. 2009 Jul 1;122(Pt 13):2240-51. doi: 10.1242/jcs.042747. Epub 2009 Jun, 9. PMID:19509060 doi:10.1242/jcs.042747
- ↑ Jang CY, Coppinger JA, Seki A, Yates JR 3rd, Fang G. Plk1 and Aurora A regulate the depolymerase activity and the cellular localization of Kif2a. J Cell Sci. 2009 May 1;122(Pt 9):1334-41. doi: 10.1242/jcs.044321. Epub 2009 Apr , 7. PMID:19351716 doi:10.1242/jcs.044321
- ↑ Wolfe BA, Takaki T, Petronczki M, Glotzer M. Polo-like kinase 1 directs assembly of the HsCyk-4 RhoGAP/Ect2 RhoGEF complex to initiate cleavage furrow formation. PLoS Biol. 2009 May 5;7(5):e1000110. doi: 10.1371/journal.pbio.1000110. Epub 2009, May 26. PMID:19468300 doi:10.1371/journal.pbio.1000110
- ↑ Burkard ME, Maciejowski J, Rodriguez-Bravo V, Repka M, Lowery DM, Clauser KR, Zhang C, Shokat KM, Carr SA, Yaffe MB, Jallepalli PV. Plk1 self-organization and priming phosphorylation of HsCYK-4 at the spindle midzone regulate the onset of division in human cells. PLoS Biol. 2009 May 5;7(5):e1000111. doi: 10.1371/journal.pbio.1000111. Epub 2009, May 26. PMID:19468302 doi:10.1371/journal.pbio.1000111
- ↑ Elia AE, Rellos P, Haire LF, Chao JW, Ivins FJ, Hoepker K, Mohammad D, Cantley LC, Smerdon SJ, Yaffe MB. The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain. Cell. 2003 Oct 3;115(1):83-95. PMID:14532005
- ↑ Yun SM, Moulaei T, Lim D, Bang JK, Park JE, Shenoy SR, Liu F, Kang YH, Liao C, Soung NK, Lee S, Yoon DY, Lim Y, Lee DH, Otaka A, Appella E, McMahon JB, Nicklaus MC, Burke TR Jr, Yaffe MB, Wlodawer A, Lee KS. Structural and functional analyses of minimal phosphopeptides targeting the polo-box domain of polo-like kinase 1. Nat Struct Mol Biol. 2009 Aug;16(8):876-82. Epub 2009 Jul 13. PMID:19597481 doi:10.1038/nsmb.1628
- ↑ Hymel D, Tsuji K, Grant RA, Chingle RM, Kunciw DL, Yaffe MB, Burke TR Jr. Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain - binding peptide macrocycles. Org Biomol Chem. 2021 Sep 22;19(36):7843-7854. PMID:34346472 doi:10.1039/d1ob01120k
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