G proteins, effectors and GAPs: structure and mechanism.

G proteins from a diverse family of regulatory GTPases which, in the GTP-bound state, bind to and activate downstream effectors. Structures of Ras homologs bound to effector domains have revealed mechanisms by which G proteins couple GTP binding to effector activation and achieve specificity. Complexes between structurally unrelated GTPase-activating proteins with complementary G proteins suggest common mechanisms by which GTP hydrolysis is stimulated via direct interactions with conformationally labile switch regions of the G protein.

[1]  M. Hirshberg,et al.  The crystal structure of human rac1, a member of the rho-family complexed with a GTP analogue , 1997, Nature Structural Biology.

[2]  R. Goody,et al.  Formation of a Transition-State Analog of the Ras GTPase Reaction by Ras·GDP, Tetrafluoroaluminate, and GTPase-Activating Proteins , 1996, Science.

[3]  Hans Robert Kalbitzer,et al.  Structure of the Ras-binding domain of RalGEF and implications for Ras binding and signalling , 1997, Nature Structural Biology.

[4]  S. Kim,et al.  Structure of ras proteins. , 1989, Science.

[5]  Gudrun Horn,et al.  Differential Interaction of the Ras Family GTP-binding Proteins H-Ras, Rap1A, and R-Ras with the Putative Effector Molecules Raf Kinase and Ral-Guanine Nucleotide Exchange Factor , 1996, The Journal of Biological Chemistry.

[6]  A. Liljas,et al.  Three‐dimensional structure of the ribosomal translocase: elongation factor G from Thermus thermophilus. , 1994, The EMBO journal.

[7]  S H Kim,et al.  Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. , 1992, Science.

[8]  Mark S. Boguski,et al.  Proteins regulating Ras and its relatives , 1993, Nature.

[9]  A. Gilman,et al.  GAIP and RGS4 Are GTPase-Activating Proteins for the Gi Subfamily of G Protein α Subunits , 1996, Cell.

[10]  S. Harrison,et al.  Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 alpha subunit. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Michael Wulff,et al.  The structure of the Escherichia coli EF-Tu· EF-Ts complex at 2.5 Å resolution , 1996, Nature.

[12]  H. Bourne,et al.  How receptors talk to trimeric G proteins. , 1997, Current opinion in cell biology.

[13]  S Thirup,et al.  Helix unwinding in the effector region of elongation factor EF-Tu-GDP. , 1996, Structure.

[14]  M Geyer,et al.  Conformational transitions in p21ras and in its complexes with the effector protein Raf-RBD and the GTPase activating protein GAP. , 1996, Biochemistry.

[15]  A. Wittinghofer,et al.  The 2.2 Å crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with RaplA and a GTP analogue , 1995, Nature.

[16]  J. Nyborg,et al.  The crystal structure of elongation factor EF-Tu from Thermus aquaticus in the GTP conformation. , 1993, Structure.

[17]  W. Kabsch,et al.  Crystal structure of the GTPase-activating domain of human p120GAP and implications for the interaction with Ras , 1996, Nature.

[18]  R. Hilgenfeld,et al.  Crystal structure of active elongation factor Tu reveals major domain rearrangements , 1993, Nature.

[19]  S. Sprang,et al.  Structural and biochemical characterization of the GTPgammaS-, GDP.Pi-, and GDP-bound forms of a GTPase-deficient Gly42 --> Val mutant of Gialpha1. , 1997, Biochemistry.

[20]  A. Warshel,et al.  Mechanistic analysis of the observed linear free energy relationships in p21ras and related systems. , 1996, Biochemistry.

[21]  Rolf Hilgenfeld,et al.  An α to β conformational switch in EF-Tu , 1996 .

[22]  W. Kabsch,et al.  The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. , 1997, Science.

[23]  T. Steitz,et al.  The crystal structure of elongation factor G complexed with GDP, at 2.7 A resolution. , 1994, The EMBO journal.

[24]  F. McCormick,et al.  Signal transduction from multiple Ras effectors. , 1997, Current opinion in genetics & development.

[25]  S R Sprang,et al.  G protein mechanisms: insights from structural analysis. , 1997, Annual review of biochemistry.

[26]  S. Smerdon,et al.  The structure of the GTPase-activating domain from p50rhoGAP , 1997, Nature.

[27]  J. Nyborg,et al.  The GTP binding motif: variations on a theme , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[28]  S. Sprang,et al.  Structure of RGS4 Bound to AlF4 −-Activated Giα1: Stabilization of the Transition State for GTP Hydrolysis , 1997, Cell.

[29]  T. Clackson,et al.  A hot spot of binding energy in a hormone-receptor interface , 1995, Science.

[30]  D. Herschlag,et al.  Ras-catalyzed hydrolysis of GTP: a new perspective from model studies. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[31]  H. Jhoti,et al.  The structure of rat ADP-ribosylation factor-1 (ARF-1) complexed to GDP determined from two different crystal forms , 1995, Nature Structural Biology.

[32]  H. Kalbitzer,et al.  Substrate-assisted catalysis as a mechanism for GTP hydrolysis of p21ras and other GTP-binding proteins , 1995, Nature Structural Biology.

[33]  H. Bourne,et al.  Separate GTP binding and GTPase activating domains of a G alpha subunit. , 1993, Science.

[34]  S. Sprang,et al.  Structure of the GDP–Pi complex of Gly203→Ala Giα1: a mimic of the ternary product complex of Gα-catalyzed GTP hydrolysis , 1996 .

[35]  S. Smerdon,et al.  Crystal structure of a small G protein in complex with the GTPase-activating protein rhoGAP , 1997, Nature.

[36]  M. Marshall,et al.  The effector interactions of p21ras. , 1993, Trends in biochemical sciences.

[37]  P B Sigler,et al.  The 2.2 A crystal structure of transducin-alpha complexed with GTP gamma S. , 1994, Nature.

[38]  Ralf Janknecht,et al.  Ras/Rap effector specificity determined by charge reversal , 1996, Nature Structural Biology.

[39]  W. Kabsch,et al.  Refined crystal structure of the triphosphate conformation of H‐ras p21 at 1.35 A resolution: implications for the mechanism of GTP hydrolysis. , 1990, The EMBO journal.

[40]  J. Janin,et al.  AlF3 mimics the transition state of protein phosphorylation in the crystal structure of nucleoside diphosphate kinase and MgADP. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[41]  A. Wittinghofer,et al.  Quantitative structure-activity analysis correlating Ras/Raf interaction in vitro to Raf activation in vivo , 1996, Nature Structural Biology.

[42]  P. Sigler,et al.  Crystal structure of the EF-Tu˙EF-Ts complex from Thermus thermophilus , 1997, Nature Structural Biology.

[43]  H. Hamm,et al.  The 2.0 Å crystal structure of a heterotrimeric G protein , 1996, Nature.

[44]  Heidi E. Hamm,et al.  Structural determinants for activation of the α-subunit of a heterotrimeric G protein , 1994, Nature.

[45]  W. Kabsch,et al.  Crystal structure of the nuclear Ras-related protein Ran in its GDP-bound form , 1995, Nature.

[46]  S Thirup,et al.  Crystal Structure of the Ternary Complex of Phe-tRNAPhe, EF-Tu, and a GTP Analog , 1995, Science.

[47]  Lan Huang,et al.  Three-dimensional structure of the Ras-interacting domain of RalGDS , 1997, Nature Structural Biology.

[48]  S. Sprang,et al.  Tertiary and Quaternary Structural Changes in Giα1 Induced by GTP Hydrolysis , 1995, Science.

[49]  H. Hamm,et al.  GTPase mechanism of Gproteins from the 1.7-Å crystal structure of transducin α - GDP AIF−4 , 1994, Nature.

[50]  R. Stroud,et al.  Structure of the conserved GTPase domain of the signal recognition particle , 1997, Nature.

[51]  S. Sprang,et al.  The structure of the G protein heterotrimer Giα1 β 1 γ 2 , 1995, Cell.

[52]  W. Minor,et al.  Crystal structure of RhoA–GDP and its functional implications , 1997, Nature Structural Biology.

[53]  Heidi E. Hamm,et al.  The 2.2 Å crystal structure of transducin-α complexed with GTPγS , 1993, Nature.

[54]  G. Montoya,et al.  Crystal structure of the NG domain from the signal-recognition particle receptor FtsY , 1997, Nature.

[55]  P. Kraulis,et al.  Solution structure and dynamics of ras p21.GDP determined by heteronuclear three- and four-dimensional NMR spectroscopy. , 1994, Biochemistry.

[56]  A. Wittinghofer,et al.  The role of the metal ion in the p21ras catalysed GTP-hydrolysis: Mn2+ versus Mg2+. , 1997, Journal of molecular biology.

[57]  M. Koelle A new family of G-protein regulators - the RGS proteins. , 1997, Current opinion in cell biology.

[58]  Frank McCormick,et al.  The GTPase superfamily: a conserved switch for diverse cell functions , 1990, Nature.

[59]  D. Ringe,et al.  Structure of the human ADP-ribosylation factor 1 complexed with GDP , 1994, Nature.

[60]  A. Gilman,et al.  The GTPase-activating Protein RGS4 Stabilizes the Transition State for Nucleotide Hydrolysis* , 1996, The Journal of Biological Chemistry.

[61]  F. McCormick,et al.  Structural requirements for the interaction of p21ras with GAP, exchange factors, and its biological effector target. , 1993, The Journal of biological chemistry.

[62]  Katrin Rittinger,et al.  Structure at 1.65 Å of RhoA and its GTPase-activating protein in complex with a transition-state analogue , 1997, Nature.

[63]  S. Sprang,et al.  Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis. , 1994, Science.