PDBsum entry 1wer

Gtpase activation

PDB id

1wer

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Contents

			Protein chain

					324 a.a. *

			Waters ×181

* Residue conservation analysis

PDB id:

1wer

Links

Name:

Gtpase activation

Title:

Ras-gtpase-activating domain of human p120gap

Structure:

P120gap. Chain: a. Fragment: catalytic domain, residues 714 - 1047. Synonym: gap-334, gapette. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: placenta. Cellular_location: cytosol. Gene: gene fragment of p120gap. Expressed in: escherichia coli. Expression_system_taxid: 562. 3259)

Resolution:

1.60Å

R-factor:

0.221

R-free:

0.271

Authors:

K.Scheffzek,A.Lautwein,W.Kabsch,M.R.Ahmadian,A.Wittinghofer

Key ref:

K.Scheffzek et al. (1996). Crystal structure of the GTPase-activating domain of human p120GAP and implications for the interaction with Ras. Nature, 384, 591-596. PubMed id: 8955277

Date:

20-Nov-96

Release date:

31-Dec-97

PROCHECK

	Headers

	References

Protein chain

P20936 (RASA1_HUMAN) - Ras GTPase-activating protein 1 from Homo sapiens

Seq: Struc:

Seq: Struc:

Seq: Struc:					1047 a.a. 324 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.?

[IntEnz] [ExPASy] [KEGG] [BRENDA]

	Nature 384:591-596 (1996)
PubMed id: 8955277

Crystal structure of the GTPase-activating domain of human p120GAP and implications for the interaction with Ras.
K.Scheffzek, A.Lautwein, W.Kabsch, M.R.Ahmadian, A.Wittinghofer.

ABSTRACT

Ras-related GTP-binding proteins function as molecular switches which cycle between GTP-bound 'on'- and GDP-bound 'off'-states. GTP hydrolysis is the common timing mechanism that mediates the return from the 'on' to the 'off'-state. It is usually slow but can be accelerated by orders of magnitude upon interaction with GTPase-activating proteins (GAPs). In the case of Ras, a major regulator of cellular growth, point mutations are found in approximately 30% of human tumours which render the protein unable to hydrolyse GTP, even in the presence of Ras-GAPs. The first structure determination of a GTPase-activating protein reveals the catalytically active fragment of the Ras-specific p120GAP (ref. 2), GAP-334, as an elongated, exclusively helical protein which appears to represent a novel protein fold. The molecule consists of two domains, one of which contains all the residues conserved among different GAPs for Ras. From the location of conserved residues around a shallow groove in the central domain we can identify the site of interaction with Ras x GTP. This leads to a model for the interaction between Ras and GAP that satisfies numerous biochemical and genetic data on this important regulatory process.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20635345

R.Lam, V.Romanov, K.Johns, K.P.Battaile, J.Wu-Brown, J.L.Guthrie, R.P.Hausinger, E.F.Pai, and N.Y.Chirgadze (2010).
Crystal structure of a truncated urease accessory protein UreF from Helicobacter pylori.

Proteins, 78, 2839-2848.

PDB code:

3cxn

19066203

A.A.Grigorescu, J.H.Vissers, D.Ristic, Y.Z.Pigli, T.W.Lynch, C.Wyman, and P.A.Rice (2009).
Inter-subunit interactions that coordinate Rad51's activities.

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Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration.

Proc Natl Acad Sci U S A, 106, 15610-15615.

PDB code:

3ig3

19433443

S.Kupzig, D.Bouyoucef-Cherchalli, S.Yarwood, R.Sessions, and P.J.Cullen (2009).
The ability of GAP1IP4BP to function as a Rap1 GTPase-activating protein (GAP) requires its Ras GAP-related domain and an arginine finger rather than an asparagine thumb.

Mol Cell Biol, 29, 3929-3940.

19321438

V.B.Kurella, J.M.Richard, C.L.Parke, L.F.Lecour, H.D.Bellamy, and D.K.Worthylake (2009).
Crystal Structure of the GTPase-activating Protein-related Domain from IQGAP1.

J Biol Chem, 284, 14857-14865.

PDB code:

3fay

19843518

Y.Tong, P.K.Hota, J.Y.Penachioni, M.B.Hamaneh, S.Kim, R.S.Alviani, L.Shen, H.He, W.Tempel, L.Tamagnone, H.W.Park, and M.Buck (2009).
Structure and function of the intracellular region of the plexin-b1 transmembrane receptor.

J Biol Chem, 284, 35962-35972.

PDB code:

3hm6

18603529

J.M.Cox, H.Li, E.A.Wood, S.Chitteni-Pattu, R.B.Inman, and M.M.Cox (2008).
Defective Dissociation of a "Slow" RecA Mutant Protein Imparts an Escherichia coli Growth Defect.

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Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase.

EMBO J, 27, 2239-2249.

PDB codes:

3dpt 3dpu

18323856

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EMBO Rep, 9, 350-355.

PDB code:

3bxj

17160901

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J.M.Cox, S.N.Abbott, S.Chitteni-Pattu, R.B.Inman, and M.M.Cox (2006).
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S.Kupzig, D.Deaconescu, D.Bouyoucef, S.A.Walker, Q.Liu, C.L.Polte, O.Daumke, T.Ishizaki, P.J.Lockyer, A.Wittinghofer, and P.J.Cullen (2006).
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J Biol Chem, 281, 9891-9900.

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D.Segal, and M.Eisenstein (2005).
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Proteins, 59, 580-591.

16055703

J.R.Basile, T.Afkhami, and J.S.Gutkind (2005).
Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway.

Mol Cell Biol, 25, 6889-6898.

15162493

A.Berchanski, B.Shapira, and M.Eisenstein (2004).
Hydrophobic complementarity in protein-protein docking.

Proteins, 56, 130-142.

15507211

B.Canagarajah, F.C.Leskow, J.Y.Ho, H.Mischak, L.F.Saidi, M.G.Kazanietz, and J.H.Hurley (2004).
Structural mechanism for lipid activation of the Rac-specific GAP, beta2-chimaerin.

Cell, 119, 407-418.

PDB code:

1xa6

12618308

A.Bernards (2003).
GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila.

Biochim Biophys Acta, 1603, 47-82.

12704243

C.F.Becker, C.L.Hunter, R.Seidel, S.B.Kent, R.S.Goody, and M.Engelhard (2003).
Total chemical synthesis of a functional interacting protein pair: the protooncogene H-Ras and the Ras-binding domain of its effector c-Raf1.

Proc Natl Acad Sci U S A, 100, 5075-5080.

14635129

J.M.Petock, I.Y.Torshin, I.T.Weber, and R.W.Harrison (2003).
Analysis of protein structures reveals regions of rare backbone conformation at functional sites.

Proteins, 53, 872-879.

11812785

Z.Wang, C.P.Tseng, R.C.Pong, H.Chen, J.D.McConnell, N.Navone, and J.T.Hsieh (2002).
The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2.

J Biol Chem, 277, 12622-12631.

11779797

B.E.Xu, K.R.Skowronek, and J.Kurjan (2001).
The N terminus of Saccharomyces cerevisiae Sst2p plays an RGS-domain-independent, Mpt5p-dependent role in recovery from pheromone arrest.

Genetics, 159, 1559-1571.

11386077

J.Ricard (2001).
Binding energy and the information content of some elementary biological processes.

C R Acad Sci III, 324, 297-304.

11013213

A.Rak, R.Fedorov, K.Alexandrov, S.Albert, R.S.Goody, D.Gallwitz, and A.J.Scheidig (2000).
Crystal structure of the GAP domain of Gyp1p: first insights into interaction with Ypt/Rab proteins.

EMBO J, 19, 5105-5113.

PDB code:

1fkm

10799524

B.C.Low, K.T.Seow, and G.R.Guy (2000).
Evidence for a novel Cdc42GAP domain at the carboxyl terminus of BNIP-2.

J Biol Chem, 275, 14415-14422.

11052931

M.B.Kennedy (2000).
Signal-processing machines at the postsynaptic density.

Science, 290, 750-754.

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N.Vitale, W.A.Patton, J.Moss, M.Vaughan, R.J.Lefkowitz, and R.T.Premont (2000).
GIT proteins, A novel family of phosphatidylinositol 3,4, 5-trisphosphate-stimulated GTPase-activating proteins for ARF6.

J Biol Chem, 275, 13901-13906.

10722686

X.Du, H.Frei, and S.H.Kim (2000).
The mechanism of GTP hydrolysis by Ras probed by Fourier transform infrared spectroscopy.

J Biol Chem, 275, 8492-8500.

10371466

H.LeVine (1999).
Structural features of heterotrimeric G-protein-coupled receptors and their modulatory proteins.

Mol Neurobiol, 19, 111-149.

10196249

M.Huber, K.A.Watson, H.C.Selinka, C.M.Carthy, K.Klingel, B.M.McManus, and R.Kandolf (1999).
Cleavage of RasGAP and phosphorylation of mitogen-activated protein kinase in the course of coxsackievirus B3 replication.

J Virol, 73, 3587-3594.

10364218

M.Sekimata, Y.Kabuyama, Y.Emori, and Y.Homma (1999).
Morphological changes and detachment of adherent cells induced by p122, a GTPase-activating protein for Rho.

J Biol Chem, 274, 17757-17762.

10085118

N.P.Skiba, C.S.Yang, T.Huang, H.Bae, and H.E.Hamm (1999).
The alpha-helical domain of Galphat determines specific interaction with regulator of G protein signaling 9.

J Biol Chem, 274, 8770-8778.

10232922

P.J.Sheffield, U.Derewenda, J.Taylor, T.J.Parsons, and Z.S.Derewenda (1999).
Expression, purification and crystallization of a BH domain from the GTPase regulatory protein associated with focal adhesion kinase.

Acta Crystallogr D Biol Crystallogr, 55, 356-359.

10394366

R.C.Hillig, L.Renault, I.R.Vetter, T.Drell, A.Wittinghofer, and J.Becker (1999).
The crystal structure of rna1p: a new fold for a GTPase-activating protein.

Mol Cell, 3, 781-791.

PDB code:

1yrg

9545275

B.A.Sermon, P.N.Lowe, M.Strom, and J.F.Eccleston (1998).
The importance of two conserved arginine residues for catalysis by the ras GTPase-activating protein, neurofibromin.

J Biol Chem, 273, 9480-9485.

9632678

D.A.Leonard, R.Lin, R.A.Cerione, and D.Manor (1998).
Biochemical studies of the mechanism of action of the Cdc42-GTPase-activating protein.

J Biol Chem, 273, 16210-16215.

9546212

E.F.Pai (1998).
The alpha and beta of turning on a molecular switch.

Nat Struct Biol, 5, 259-263.

9697416

K.Scheffzek, M.R.Ahmadian, and A.Wittinghofer (1998).
GTPase-activating proteins: helping hands to complement an active site.

Trends Biochem Sci, 23, 257-262.

9687500

K.Scheffzek, M.R.Ahmadian, L.Wiesmüller, W.Kabsch, P.Stege, F.Schmitz, and A.Wittinghofer (1998).
Structural analysis of the GAP-related domain from neurofibromin and its implications.

EMBO J, 17, 4313-4327.

PDB code:

1nf1

9651538

M.B.Kennedy (1998).
Signal transduction molecules at the glutamatergic postsynaptic membrane.

Brain Res Brain Res Rev, 26, 243-257.

9506972

M.Natochin, R.L.McEntaffer, and N.O.Artemyev (1998).
Mutational analysis of the Asn residue essential for RGS protein binding to G-proteins.

J Biol Chem, 273, 6731-6735.

9852136

N.Tatsis, D.A.Lannigan, and I.G.Macara (1998).
The function of the p190 Rho GTPase-activating protein is controlled by its N-terminal GTP binding domain.

J Biol Chem, 273, 34631-34638.

9446556

N.Vitale, J.Moss, and M.Vaughan (1998).
Molecular characterization of the GTPase-activating domain of ADP-ribosylation factor domain protein 1 (ARD1).

J Biol Chem, 273, 2553-2560.

9631293

S.J.Gamblin, and S.J.Smerdon (1998).
GTPase-activating proteins and their complexes.

Curr Opin Struct Biol, 8, 195-201.

9430692

S.P.Srinivasa, N.Watson, M.C.Overton, and K.J.Blumer (1998).
Mechanism of RGS4, a GTPase-activating protein for G protein alpha subunits.

J Biol Chem, 273, 1529-1533.

9334333

A.Hajnal, C.W.Whitfield, and S.K.Kim (1997).
Inhibition of Caenorhabditis elegans vulval induction by gap-1 and by let-23 receptor tyrosine kinase.

Genes Dev, 11, 2715-2728.

9312017

J.Cherfils, J.Ménétrey, G.Le Bras, I.Janoueix-Lerosey, J.de Gunzburg, J.R.Garel, and I.Auzat (1997).
Crystal structures of the small G protein Rap2A in complex with its substrate GTP, with GDP and with GTPgammaS.

EMBO J, 16, 5582-5591.

PDB codes:

1kao 2rap

9302988

J.P.Noel (1997).
Turning off the Ras switch with the flick of a finger.

Nat Struct Biol, 4, 677-680.

9667874

J.P.Wery, and R.W.Schevitz (1997).
New trends in macromolecular X-ray crystallography.

Curr Opin Chem Biol, 1, 365-369.

9219684

K.Scheffzek, M.R.Ahmadian, W.Kabsch, L.Wiesmüller, A.Lautwein, F.Schmitz, and A.Wittinghofer (1997).
The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants.

Science, 277, 333-338.

PDB code:

1wq1

9434896

M.Geyer, and A.Wittinghofer (1997).
GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins.

Curr Opin Struct Biol, 7, 786-792.

9302992

M.R.Ahmadian, P.Stege, K.Scheffzek, and A.Wittinghofer (1997).
Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras.

Nat Struct Biol, 4, 686-689.

9348541

R.T.Müller, U.Honnert, J.Reinhard, and M.Bähler (1997).
The rat myosin myr 5 is a GTPase-activating protein for Rho in vivo: essential role of arginine 1695.

Mol Biol Cell, 8, 2039-2053.

9242920

S.R.Sprang (1997).
G protein mechanisms: insights from structural analysis.

Annu Rev Biochem, 66, 639-678.

9434906

S.R.Sprang (1997).
G proteins, effectors and GAPs: structure and mechanism.

Curr Opin Struct Biol, 7, 849-856.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.