title: Dynamic circadian protein-protein interaction networks predict temporal organization of cellular functions.
abstract: Essentially all biological processes depend on protein-protein interactions (PPIs). Timing of such interactions is crucial for regulatory function. Although circadian (~24-hour) clocks constitute fundamental cellular timing mechanisms regulating important physiological processes, PPI dynamics on this timescale are largely unknown. Here, we identified 109 novel PPIs among circadian clock proteins via a yeast-two-hybrid approach. Among them, the interaction of protein phosphatase 1 and CLOCK/BMAL1 was found to result in BMAL1 destabilization. We constructed a dynamic circadian PPI network predicting the PPI timing using circadian expression data. Systematic circadian phenotyping (RNAi and overexpression) suggests a crucial role for components involved in dynamic interactions. Systems analysis of a global dynamic network in liver revealed that interacting proteins are expressed at similar times likely to restrict regulatory interactions to specific phases. Moreover, we predict that circadian PPIs dynamically connect many important cellular processes (signal transduction, cell cycle, etc.) contributing to temporal organization of cellular physiology in an unprecedented manner.
authors.affiliation: Laboratory of Chronobiology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wallach
authors.forename: Katja
authors.initials: K
authors.lastname: Schellenberg
authors.forename: Bert
authors.initials: B
authors.lastname: Maier
authors.forename: Ravi Kiran Reddy
authors.initials: RK
authors.lastname: Kalathur
authors.forename: Pablo
authors.initials: P
authors.lastname: Porras
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Futschik
authors.forename: Achim
authors.initials: A
authors.lastname: Kramer
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D060066:Protein Interaction Maps / Q000235:genetics*; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D056926:CLOCK Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D054645:Protein Phosphatase 1
references.citation: Cell. 2005 Sep 23;122(6):957-68
references.pmid: 16169070
references.citation: Nat Struct Mol Biol. 2010 Dec;17(12):1414-21
references.pmid: 21113167
references.citation: Mol Syst Biol. 2010 Aug 24;6:400
references.pmid: 20739923
references.citation: Bioinformatics. 2008 Apr 15;24(8):1063-9
references.pmid: 18310054
references.citation: Nat Rev Mol Cell Biol. 2007 Feb;8(2):139-48
references.pmid: 17245414
references.citation: Nat Cell Biol. 2007 Mar;9(3):268-75
references.pmid: 17310242
references.citation: PLoS Genet. 2009 Apr;5(4):e1000442
references.pmid: 19343201
references.citation: Nature. 2002 Oct 24;419(6909):841-4
references.pmid: 12397359
references.citation: Science. 2005 Apr 29;308(5722):693-6
references.pmid: 15860628
references.citation: Science. 2011 Jun 17;332(6036):1436-9
references.pmid: 21680841
references.citation: Cell. 2008 Jul 25;134(2):317-28
references.pmid: 18662546
references.citation: Science. 2010 Jan 22;327(5964):463-6
references.pmid: 20093473
references.citation: Curr Biol. 2006 Jun 6;16(11):1107-15
references.pmid: 16753565
references.citation: Science. 2008 Nov 7;322(5903):923-9
references.pmid: 18988848
references.citation: Science. 2005 Feb 4;307(5710):724-7
references.pmid: 15692050
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18560-5
references.pmid: 22042857
references.citation: Nature. 2002 May 2;417(6884):78-83
references.pmid: 11967526
references.citation: Mol Cell. 2004 Sep 24;15(6):853-65
references.pmid: 15383276
references.citation: Nat Rev Genet. 2004 Feb;5(2):101-13
references.pmid: 14735121
references.citation: PLoS One. 2011;6(6):e21325
references.pmid: 21712997
references.citation: Mol Syst Biol. 2010 Dec 21;6:450
references.pmid: 21179022
references.citation: Genes Dev. 2003 Aug 1;17(15):1921-32
references.pmid: 12897057
references.citation: Science. 2011 Sep 30;333(6051):1881-5
references.pmid: 21960634
references.citation: Mol Biol Evol. 2005 Apr;22(4):803-6
references.pmid: 15616139
references.citation: Nat Rev Mol Cell Biol. 2010 Nov;11(11):764-76
references.pmid: 20966970
references.citation: Genes Dev. 2009 Mar 15;23(6):708-18
references.pmid: 19299560
references.citation: Nature. 2002 Aug 29;418(6901):935-41
references.pmid: 12198538
references.citation: Cell. 2001 Dec 28;107(7):855-67
references.pmid: 11779462
references.citation: Nat Methods. 2009 Jan;6(1):91-7
references.pmid: 19060903
references.citation: Mol Cell Biol. 2009 Jul;29(13):3675-86
references.pmid: 19414601
references.citation: Curr Opin Chem Biol. 2006 Dec;10(6):551-8
references.pmid: 17055769
references.citation: PLoS Biol. 2011 Feb;9(2):e1000595
references.pmid: 21364973
references.citation: Cell. 2009 Oct 2;139(1):199-210
references.pmid: 19765810
references.citation: FEBS Lett. 2011 May 20;585(10):1393-9
references.pmid: 21376720
references.citation: Science. 1998 Jun 5;280(5369):1564-9
references.pmid: 9616112
references.citation: Nature. 2004 Jul 1;430(6995):88-93
references.pmid: 15190252
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16451-6
references.pmid: 21930935
references.citation: Science. 2008 Nov 7;322(5903):918-23
references.pmid: 18988847
references.citation: Cell. 2002 May 3;109(3):307-20
references.pmid: 12015981
references.citation: Nature. 2011 May 19;473(7347):337-42
references.pmid: 21593866
references.citation: PLoS One. 2010 Jan 01;5(1):e8561
references.pmid: 20049328
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D590-4
references.pmid: 17158159
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D657-60
references.pmid: 18984619
references.citation: Nature. 2001 Mar 8;410(6825):268-76
references.pmid: 11258382
references.citation: Trends Biochem Sci. 2006 Sep;31(9):497-508
references.pmid: 16890441