title: Identification of potential Plk1 targets in a cell-cycle specific proteome through structural dynamics of kinase and Polo box-mediated interactions.
abstract: Polo like kinase 1 (Plk1) is a key player in orchestrating the wide variety of cell-cycle events ranging from centrosome maturation, mitotic entry, checkpoint recovery, transcriptional control, spindle assembly, mitotic progression, cytokinesis and DNA damage checkpoints recovery. Due to its versatile nature, Plk1 is considered an imperative regulator to tightly control the diverse aspects of the cell cycle network. Interactions among Plk1 polo box domain (PBD) and its putative binding proteins are crucial for the activation of Plk1 kinase domain (KD). To date, only a few substrate candidates have been characterized through the inclusion of both polo box and kinase domain-mediated interactions. Thus it became compelling to explore precise and specific Plk1 substrates through reassessment and extension of the structure-function paradigm. To narrow this apparently wide gap in knowledge, here we employed a thorough sequence search of Plk1 phosphorylation signature containing proteins and explored their structure-based features like conceptual PBD-binding capabilities and subsequent recruitment of KD directed phosphorylation to dissect novel targets of Plk1. Collectively, we identified 4,521 phosphodependent proteins sharing similarity to the consensus phosphorylation and PBD recognition motifs. Subsequent application of filters including similarity index, Gene Ontology enrichment and protein localization resulted in stringent pre-filtering of irrelevant candidates and isolated unique targets with well-defined roles in cell-cycle machinery and carcinogenesis. These candidates were further refined structurally using molecular docking and dynamic simulation assays. Overall, our screening approach enables the identification of several undefined cell-cycle associated functions of Plk1 by uncovering novel phosphorylation targets.
authors: National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
authors: Nousheen
authors: N
authors: Bibi
authors: Zahida
authors: Z
authors: Parveen
authors: Sajid
authors: S
authors: Rashid
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D013379:Substrate Specificity; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D020543:Proteome; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1
references: PLoS Biol. 2005 Dec;3(12):e405
references: 16279839
references: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references: 8744570
references: Dev Cell. 2003 Jul;5(1):127-38
references: 12852857
references: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12589-94
references: 11050165
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D690-7
references: 19033362
references: EMBO J. 2003 Nov 3;22(21):5757-68
references: 14592974
references: Biochem Biophys Res Commun. 2004 Dec 24;325(4):1443-8
references: 15555589
references: Mol Cell Proteomics. 2010 Jun;9(6):1167-81
references: 20097925
references: Cell Cycle. 2006 Apr;5(8):853-64
references: 16627997
references: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4124-9
references: 15037762
references: Chem Biol. 2007 Nov;14(11):1261-72
references: 18022565
references: Bioinformatics. 2007 Nov 1;23(21):2947-8
references: 17846036
references: BMC Bioinformatics. 2004 Jun 22;5:79
references: 15212693
references: Nat Cell Biol. 2003 Feb;5(2):143-8
references: 12524548
references: J Mol Biol. 1993 Dec 5;234(3):779-815
references: 8254673
references: Bioinformatics. 2000 Apr;16(4):404-5
references: 10869041
references: Protein Cell. 2010 Nov;1(11):999-1010
references: 21153517
references: J Comput Chem. 2009 Dec;30(16):2785-91
references: 19399780
references: Proteomics. 2004 Jun;4(6):1633-49
references: 15174133
references: Genes Dev. 1991 Dec;5(12A):2153-65
references: 1660828
references: Curr Opin Cell Biol. 1998 Dec;10(6):776-83
references: 9914175
references: Cell. 2003 Oct 3;115(1):83-95
references: 14532005
references: Mol Cell Biol. 1995 Dec;15(12):7143-51
references: 8524282
references: PLoS One. 2007 May 02;2(5):e409
references: 17476331
references: BMC Bioinformatics. 2008 Jan 23;9:40
references: 18215316
references: Nat Rev Mol Cell Biol. 2004 Jun;5(6):429-40
references: 15173822
references: Cell Div. 2012 Feb 06;7:3
references: 22309699
references: Mol Cell Biol. 2002 Sep;22(17):6209-21
references: 12167714
references: Nat Genet. 2000 May;25(1):25-9
references: 10802651
references: J Mol Graph. 1990 Mar;8(1):52-6, 29
references: 2268628
references: J Biol Chem. 1995 Sep 8;270(36):21086-91
references: 7673138
references: Methods Enzymol. 1997;277:396-404
references: 9379925
references: Mol Syst Biol. 2007;3:88
references: 17353930
references: PLoS One. 2011 Jan 06;6(1):e15928
references: 21253604
references: Prog Cell Cycle Res. 1995;1:187-205
references: 9552363
references: J Biol Chem. 2003 Aug 8;278(32):29471-7
references: 12775710
references: J Cell Sci. 2004 Jul 1;117(Pt 15):3233-46
references: 15199097
references: Science. 2008 Jun 20;320(5883):1655-8
references: 18566290
references: PLoS One. 2009 Aug 03;4(8):e6476
references: 19649298
references: Nature. 2008 Sep 4;455(7209):119-23
references: 18615013
references: BMC Bioinformatics. 2006 Jul 12;7:339
references: 16836757
references: J Biol Chem. 2002 Nov 15;277(46):44115-20
references: 12207013
references: Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
references: 20383002
references: Cell Mol Life Sci. 2010 Jun;67(12):1957-70
references: 20148280
references: J Cell Sci. 2001 Jul;114(Pt 13):2357-8
references: 11559744
references: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1984-9
references: 11854496
references: EMBO J. 2007 May 2;26(9):2262-73
references: 17446864
references: Mol Cell. 2006 Nov 3;24(3):409-22
references: 17081991
references: J Biol Chem. 2003 Sep 19;278(38):35979-87
references: 12815053
references: Genes Dev. 1998 Dec 15;12(24):3777-87
references: 9869630
references: Oncogene. 2005 Jan 10;24(2):248-59
references: 15640840
references: Oncogene. 2005 Jan 10;24(2):230-7
references: 15640838
references: Protein Eng. 1995 Feb;8(2):127-34
references: 7630882
references: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4419-24
references: 15070733
references: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references: 9254694
references: Cancer Inform. 2008;6:257-73
references: 19259413
references: Nature. 2001 Mar 8;410(6825):215-20
references: 11242082
references: Curr Opin Cell Biol. 2008 Dec;20(6):650-60
references: 19000759
references: Dev Cell. 2003 Jul;5(1):113-25
references: 12852856
references: J Cell Biol. 2003 Sep 1;162(5):863-75
references: 12939256
references: J Biol Chem. 2003 Jul 11;278(28):25277-80
references: 12738781
references: Mol Cell Biol. 2009 May;29(10):2609-21
references: 19289504
references: Protein Sci. 1993 Sep;2(9):1511-9
references: 8401235
references: Chromosoma. 2010 Apr;119(2):137-47
references: 19997740
references: Plant J. 2011 Sep;67(6):993-1005
references: 21605211
references: J Comput Chem. 2003 Dec;24(16):1999-2012
references: 14531054
references: J Cell Sci. 1988 Jan;89 ( Pt 1):25-38
references: 3417791
references: Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9128-32
references: 11447294
references: Nat Rev Mol Cell Biol. 2009 Apr;10(4):265-75
references: 19305416
references: Genome Biol. 2008 Jan 30;9(1):203
references: 18254925
references: Hepatology. 2010 Mar;51(3):857-68
references: 20112253
references: Bioinformatics. 2013 Mar 15;29(6):807-9
references: 23343604
references: Mol Cell Proteomics. 2011 Jan;10(1):M110.004457
references: 20860994
references: J Am Chem Soc. 2003 Feb 19;125(7):1731-7
references: 12580598
references: Biofizika. 2012 Mar-Apr;57(2):197-204
references: 22594273
references: Proteins. 2008 Aug;72(2):547-56
references: 18247410
references: Mol Biol Cell. 2005 Mar;16(3):1095-107
references: 15616186