title: Integration of the accelerator Aha1 in the Hsp90 co-chaperone cycle.
abstract: Heat-shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that associates dynamically with various co-chaperones during its chaperone cycle. Here we analyzed the role of the activating co-chaperone Aha1 in the progression of the yeast Hsp90 chaperone cycle and identified a critical ternary Hsp90 complex containing the co-chaperones Aha1 and Cpr6. Aha1 accelerates the intrinsically slow conformational transitions of Hsp90 to an N-terminally associated state but does not fully close the nucleotide-binding pocket yet. Cpr6 increases the affinity between Aha1 and Hsp90 and further stimulates the Hsp90 ATPase activity. Synergistically, Aha1 and Cpr6 displace the inhibitory co-chaperone Sti1 from Hsp90. To complete the cycle, Aha1 is released by the co-chaperone p23. Thus, at distinct steps during the Hsp90 chaperone cycle, co-chaperones selectively trap statistically distributed Hsp90 conformers and thus turn Hsp90 into a deterministic machine.
authors: Center for Integrated Protein Science, Department Chemie, Technische Universität München, München, Germany.
authors: Jing
authors: J
authors: Li
authors: Klaus
authors: K
authors: Richter
authors: Jochen
authors: J
authors: Reinstein
authors: Johannes
authors: J
authors: Buchner
mesh_terms: D001667:Binding, Competitive; D018833:Chaperonins / Q000737:chemistry* / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000737:chemistry / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism*; D000097322:Peptidyl-Prolyl Isomerase D
chemical_list: D018833:Chaperonins; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; C475092:AHA1 protein, S cerevisiae; C000631444:CPR6 protein, S cerevisiae; D000097322:Peptidyl-Prolyl Isomerase D; C113025:SBA1 protein, S cerevisiae; C542289:STI1 protein, S cerevisiae
references: J Biol Chem. 2001 Sep 7;276(36):33689-96
references: 11441008
references: Mol Cell. 2002 Dec;10(6):1255-6
references: 12503997
references: Science. 1996 Dec 6;274(5293):1713-5
references: 8939862
references: Mol Cell. 2008 Dec 5;32(5):631-40
references: 19061638
references: Nat Struct Mol Biol. 2011 Jan;18(1):61-6
references: 21170051
references: Nature. 2006 Apr 20;440(7087):1013-7
references: 16625188
references: Mol Cell. 2010 Sep 24;39(6):912-924
references: 20864038
references: Mol Cell. 2010 Oct 22;40(2):253-66
references: 20965420
references: Proc Natl Acad Sci U S A. 2012 Jan 3;109(1):161-6
references: 22184223
references: J Biol Chem. 2008 Jun 27;283(26):17757-65
references: 18400751
references: J Biol Chem. 1998 Dec 25;273(52):35194-200
references: 9857057
references: Genes Dev. 2000 Feb 15;14(4):422-34
references: 10691735
references: Cell. 2006 Oct 20;127(2):329-40
references: 17055434
references: Biochemistry. 1993 Mar 16;32(10):2717-24
references: 8383523
references: Cell Mol Life Sci. 2002 Oct;59(10):1640-8
references: 12475174
references: Mol Cell. 2011 Apr 8;42(1):96-105
references: 21474071
references: Mol Endocrinol. 1993 Nov;7(11):1418-29
references: 7906860
references: Mol Cell. 2010 Feb 12;37(3):344-54
references: 20159554
references: J Mol Biol. 2002 Jan 25;315(4):787-98
references: 11812147
references: EMBO J. 2000 Aug 15;19(16):4383-92
references: 10944121
references: Biochim Biophys Acta. 2012 Mar;1823(3):614-23
references: 21840346
references: J Biol Chem. 2011 Apr 1;286(13):11091-8
references: 21278257
references: J Steroid Biochem Mol Biol. 1996 Jan;56(1-6 Spec No):31-7
references: 8603045
references: J Biol Chem. 1998 Dec 4;273(49):32973-9
references: 9830049
references: Biochem J. 2005 May 1;387(Pt 3):789-96
references: 15584899
references: Nat Struct Mol Biol. 2009 Nov;16(11):1141-7
references: 19838189
references: Biochim Biophys Acta. 2012 Mar;1823(3):624-35
references: 21951723
references: J Biol Chem. 2000 Nov 3;275(44):34140-6
references: 10942767
references: Genetics. 2012 Jul;191(3):805-14
references: 22505624
references: J Cell Biol. 2001 Jul 23;154(2):267-73
references: 11470816
references: J Mol Biol. 2000 Nov 3;303(4):583-92
references: 11054293
references: Anal Biochem. 2009 Jul 1;390(1):1-13
references: 19103145
references: Methods Enzymol. 1998;290:418-29
references: 9534179
references: Nat Immunol. 2007 May;8(5):497-503
references: 17435760
references: Nat Struct Mol Biol. 2011 Sep 04;18(10):1086-93
references: 21892170
references: Annu Rev Biophys Biomol Struct. 1999;28:75-100
references: 10410796
references: Mol Biol Cell. 2010 Mar 15;21(6):871-84
references: 20089831
references: Mol Endocrinol. 1995 Jun;9(6):670-8
references: 8592513
references: J Mol Biol. 2006 Feb 24;356(3):746-58
references: 16403413
references: Oncotarget. 2011 Jan-Feb;2(1-2):43-58
references: 21378414
references: Science. 1999 Aug 6;285(5429):901-6
references: 10436161
references: Cell. 2007 Oct 5;131(1):121-35
references: 17923092
references: Nat Struct Mol Biol. 2011 May;18(5):537-41
references: 21460846
references: J Biol Chem. 2003 Mar 21;278(12):10328-33
references: 12525481
references: Nat Struct Mol Biol. 2009 Mar;16(3):287-93
references: 19234467
references: Cell. 2005 Mar 11;120(5):715-27
references: 15766533
references: Mol Cell. 2002 Dec;10(6):1307-18
references: 12504007
references: Nat Rev Mol Cell Biol. 2010 Jul;11(7):515-28
references: 20531426
references: Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):17939-44
references: 22011577