title: Multiple factors confer specific Cdc42 and Rac protein activation by dedicator of cytokinesis (DOCK) nucleotide exchange factors.
abstract: DOCK (dedicator of cytokinesis) guanine nucleotide exchange factors (GEFs) activate the Rho-family GTPases Rac and Cdc42 to control cell migration, morphogenesis, and phagocytosis. The DOCK A and B subfamilies activate Rac, whereas the DOCK D subfamily activates Cdc42. Nucleotide exchange is catalyzed by a conserved DHR2 domain (DOCK(DHR2)). Although the molecular basis for DOCK(DHR2)-mediated GTPase activation has been elucidated through structures of a DOCK9(DHR2)-Cdc42 complex, the factors determining recognition of specific GTPases are unknown. To understand the molecular basis for DOCK-GTPase specificity, we have determined the crystal structure of DOCK2(DHR2) in complex with Rac1. DOCK2(DHR2) and DOCK9(DHR2) exhibit similar tertiary structures and homodimer interfaces and share a conserved GTPase-activating mechanism. Multiple structural differences between DOCK2(DHR2) and DOCK9(DHR2) account for their selectivity toward Rac1 and Cdc42. Key determinants of selectivity of Cdc42 and Rac for their cognate DOCK(DHR2) are a Phe or Trp residue within β3 (residue 56) and the ability of DOCK proteins to exploit differences in the GEF-induced conformational changes of switch 1 dependent on a divergent residue at position 27. DOCK proteins, therefore, differ from DH-PH GEFs that select their cognate GTPases through recognition of structural differences within the β2/β3 strands.
authors: Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, United Kingdom.
authors: Kiran
authors: K
authors: Kulkarni
authors: Jing
authors: J
authors: Yang
authors: Ziguo
authors: Z
authors: Zhang
authors: David
authors: D
authors: Barford
references: Dev Cell. 2001 Oct;1(4):491-502
references: 11703940
references: Genes Dev. 1998 Nov 1;12(21):3331-6
references: 9808620
references: Biochem J. 2008 Jan 15;409(2):525-33
references: 17935486
references: J Biol Chem. 2001 Dec 14;276(50):47530-41
references: 11595749
references: Methods Enzymol. 2006;406:41-57
references: 16472648
references: Nat Struct Biol. 2001 Dec;8(12):1037-41
references: 11685227
references: Nat Struct Biol. 1998 Dec;5(12):1047-52
references: 9846874
references: Biochemistry. 2011 Feb 15;50(6):1070-80
references: 21033699
references: Curr Biol. 2005 Feb 22;15(4):371-7
references: 15723800
references: Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
references: 15299374
references: Science. 2001 Nov 9;294(5545):1299-304
references: 11701921
references: Nat Rev Mol Cell Biol. 2008 Sep;9(9):690-701
references: 18719708
references: Cell. 2001 Oct 5;107(1):27-41
references: 11595183
references: Dev Cell. 2001 Oct;1(4):477-89
references: 11703939
references: J Cell Sci. 2005 Nov 1;118(Pt 21):4937-46
references: 16254241
references: Mol Cell Biol. 2006 Dec;26(24):9442-55
references: 17030600
references: Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21
references: 9757107
references: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W375-83
references: 17452350
references: Mol Biol Cell. 2008 Nov;19(11):4837-51
references: 18768751
references: Curr Biol. 2008 Oct 14;18(19):1456-65
references: 18835169
references: Nat Protoc. 2007;2(4):924-32
references: 17446874
references: J Biol Chem. 2004 Sep 3;279(36):37470-6
references: 15247287
references: J Biol Chem. 2008 May 16;283(20):14153-64
references: 18348980
references: EMBO J. 2003 Mar 3;22(5):1125-33
references: 12606577
references: Nat Cell Biol. 2002 Sep;4(9):639-47
references: 12172552
references: Biochem J. 2001 Feb 15;354(Pt 1):73-8
references: 11171081
references: Nat Cell Biol. 2005 Aug;7(8):797-807
references: 16025104
references: Nat Rev Mol Cell Biol. 2005 Feb;6(2):167-80
references: 15688002
references: Mol Cell Biol. 1996 Apr;16(4):1770-6
references: 8657152
references: J Cell Sci. 2002 Dec 15;115(Pt 24):4901-13
references: 12432077
references: Gene. 1997 Feb 20;186(1):29-35
references: 9047341
references: Annu Rev Cell Dev Biol. 2005;21:247-69
references: 16212495
references: J Biol Chem. 1998 Sep 18;273(38):24479-84
references: 9733740
references: Trends Cell Biol. 2007 Aug;17(8):383-93
references: 17765544
references: Bioinformatics. 2006 Jan 15;22(2):195-201
references: 16301204
references: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references: 15572765
references: Cell. 2007 Jun 29;129(7):1430
references: 17604728
references: Acta Crystallogr D Biol Crystallogr. 2002 Nov;58(Pt 11):1948-54
references: 12393927
references: J Biol Chem. 2010 Apr 23;285(17):13211-22
references: 20167601
references: Nat Struct Biol. 2002 Jun;9(6):468-75
references: 12006984
references: Nat Cell Biol. 2002 Aug;4(8):574-82
references: 12134158
references: Cell. 2007 Jun 1;129(5):865-77
references: 17540168
references: Acta Crystallogr D Biol Crystallogr. 2004 Mar;60(Pt 3):432-8
references: 14993666
references: Science. 2009 Sep 11;325(5946):1398-402
references: 19745154
references: Blood. 2003 Oct 15;102(8):2948-50
references: 12829596
references: J Biol Chem. 2008 Feb 8;283(6):3088-3096
references: 18056264
references: J Cell Biol. 1999 Sep 6;146(5):1107-16
references: 10477763
references: Protein Sci. 1999 Apr;8(4):778-87
references: 10211824
references: Exp Cell Res. 2007 Feb 15;313(4):791-804
references: 17196961
references: Nat Struct Biol. 1997 Feb;4(2):147-52
references: 9033596
references: Cell. 2008 Oct 31;135(3):510-23
references: 18984162