Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B

被引：144

作者：

Rehmann, Holger ^{[1
,2
]}

Arias-Palomo, Ernesto ^{[3
]}

Hadders, Michael A. ^{[4
]}

Schwede, Frank ^{[5
]}

Llorca, Oscar ^{[3
]}

Bos, Johannes L. ^{[1
,2
]}

机构：

[1] Univ Med Ctr, Dept Physiol Chem, Ctr Biomed Genet, NL-3584 CG Utrecht, Netherlands

[2] Univ Med Ctr, Canc Genom Ctr, NL-3584 CG Utrecht, Netherlands

[3] CSIC, CIB, Spanish Natl Res Council, E-28040 Madrid, Spain

[4] Univ Utrecht, Bijvoet Ctr, Dept Crystal & Struct Chem, NL-3584 CH Utrecht, Netherlands

[5] BIOLOG Life Sci Inst, D-28199 Bremen, Germany

来源：

NATURE | 2008年 / 455卷 / 7209期

关键词：

D O I：

10.1038/nature07187

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Epac proteins are activated by binding of the second messenger cAMP and then act as guanine nucleotide exchange factors for Rap proteins(1,2). The Epac proteins are involved in the regulation of cell adhesion(3) and insulin secretion(4). Here we have determined the structure of Epac2 in complex with a cAMP analogue (Sp-cAMPS) and RAP1B by X- ray crystallography and single particle electron microscopy. The structure represents the cAMP activated state of the Epac2 protein with the RAP1B protein trapped in the course of the exchange reaction. Comparison with the inactive conformation reveals that cAMP binding causes conformational changes that allow the cyclic nucleotide binding domain to swing from a position blocking the Rap binding site towards a docking site at the Ras exchange motif domain.

引用

页码：124 / U93

页数：5

共 35 条

[1] The structural basis of the activation of Ras by Sos [J].

Boriack-Sjodin, PA ;

Margarit, SM ;

Bar-Sagi, D ;

Kuriyan, J .

NATURE, 1998, 394 (6691) :337-343

[2] Linking Rap to cell adhesion [J].

Bos, JL .

CURRENT OPINION IN CELL BIOLOGY, 2005, 17 (02) :123-128

[3] Classification and phylogenetic analysis of the cAMP-dependent protein kinase regulatory subunit family [J].

Canaves, JM ;

Taylor, SS .

JOURNAL OF MOLECULAR EVOLUTION, 2002, 54 (01) :17-29

[4] Structural basis of ligand activation in a cyclic nucleotide regulated potassium channel [J].

Clayton, GM ;

Silverman, WR ;

Heginbotham, L ;

Morais-Cabral, JH .

CELL, 2004, 119 (05) :615-627

[5] Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP [J].

de Rooij, J ;

Zwartkruis, FJT ;

Verheijen, MHG ;

Cool, RH ;

Nijman, SMB ;

Wittinghofer, A ;

Bos, JL .

NATURE, 1998, 396 (6710) :474-477

[6] Molecular basis for regulatory subunit diversity in cAMP-dependent protein kinase:: Crystal structure of the type IIβ regulatory subunit [J].

Diller, TC ;

Madhusudan ;

Xuong, NH ;

Taylor, SS .

STRUCTURE, 2001, 9 (01) :73-82

[7] SPIDER and WEB: Processing and visualization of images in 3D electron microscopy and related fields [J].

Frank, J ;

Radermacher, M ;

Penczek, P ;

Zhu, J ;

Li, YH ;

Ladjadj, M ;

Leith, A .

JOURNAL OF STRUCTURAL BIOLOGY, 1996, 116 (01) :190-199

[8] A Ras-induced conformational switch in the Ras activator Son of sevenless [J].

Freedman, Tanya S. ;

Sondermann, Holger ;

Friedland, Gregory D. ;

Kortemme, Tanja ;

Bar-Sagil, Dafna ;

Marqusee, Susan ;

Kuriyan, John .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (45) :16692-16697

[9] ADP_EM:: fast exhaustive multi-resolution docking for high-throughput coverage [J].

Garzon, Jose Ignacio ;

Kovacs, Julio ;

Abagyan, Ruben ;

Chacon, Pablo .

BIOINFORMATICS, 2007, 23 (04) :427-433

[10] 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 [J].

Herrmann, C ;

Horn, G ;

Spaargaren, M ;

Wittinghofer, A .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (12) :6794-6800

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