Structure of Shigella IpgB2 in complex with human RhoA: implications for the mechanism of bacterial guanine nucleotide exchange factor mimicry.

2.50
Hdl Handle:
http://hdl.handle.net/10033/110236
Title:
Structure of Shigella IpgB2 in complex with human RhoA: implications for the mechanism of bacterial guanine nucleotide exchange factor mimicry.
Authors:
Klink, Björn U; Barden, Stephan; Heidler, Thomas V; Borchers, Christina; Ladwein, Markus; Stradal, Theresia E B; Rottner, Klemens; Heinz, Dirk W
Abstract:
A common theme in bacterial pathogenesis is the manipulation of eukaryotic cells by targeting the cytoskeleton. This is in most cases achieved either by modifying actin, or indirectly via activation of key regulators controlling actin dynamics such as Rho-GTPases. A novel group of bacterial virulence factors termed the WXXXE family has emerged as guanine nucleotide exchange factors (GEFs) for these GTPases. The precise mechanism of nucleotide exchange, however, has remained unclear. Here we report the structure of the WXXXE-protein IpgB2 from Shigella flexneri and its complex with human RhoA. We unambiguously identify IpgB2 as a bacterial RhoA-GEF and dissect the molecular mechanism of GDP release, an essential prerequisite for GTP binding. Our observations uncover that IpgB2 induces conformational changes on RhoA mimicking DbI- but not DOCK family GEFs. We also show that dissociation of the GDP.Mg(2+) complex is preceded by the displacement of the metal ion to the alpha-phosphate of the nucleotide, diminishing its affinity to the GTPase. These data refine our understanding of the mode of action not only of WXXXE GEFs but also of mammalian GEFs of the DH/PH family.
Affiliation:
Division of Structural Biology, Helmholtz Zentrum für Infektionsforschung, D-38124 Braunschweig, Germany.
Citation:
Structure of Shigella IpgB2 in complex with human RhoA: implications for the mechanism of bacterial guanine nucleotide exchange factor mimicry. 2010, 285 (22):17197-208 J. Biol. Chem.
Journal:
The Journal of biological chemistry
Issue Date:
28-May-2010
URI:
http://hdl.handle.net/10033/110236
DOI:
10.1074/jbc.M110.107953
PubMed ID:
20363740
Type:
Article
Language:
en
ISSN:
1083-351X
Appears in Collections:
Publications from Division of Molekulare Struktur Biologie (MOSB)

Full metadata record

DC FieldValue Language
dc.contributor.authorKlink, Björn Uen
dc.contributor.authorBarden, Stephanen
dc.contributor.authorHeidler, Thomas Ven
dc.contributor.authorBorchers, Christinaen
dc.contributor.authorLadwein, Markusen
dc.contributor.authorStradal, Theresia E Ben
dc.contributor.authorRottner, Klemensen
dc.contributor.authorHeinz, Dirk Wen
dc.date.accessioned2010-08-24T09:31:19Z-
dc.date.available2010-08-24T09:31:19Z-
dc.date.issued2010-05-28-
dc.identifier.citationStructure of Shigella IpgB2 in complex with human RhoA: implications for the mechanism of bacterial guanine nucleotide exchange factor mimicry. 2010, 285 (22):17197-208 J. Biol. Chem.en
dc.identifier.issn1083-351X-
dc.identifier.pmid20363740-
dc.identifier.doi10.1074/jbc.M110.107953-
dc.identifier.urihttp://hdl.handle.net/10033/110236-
dc.description.abstractA common theme in bacterial pathogenesis is the manipulation of eukaryotic cells by targeting the cytoskeleton. This is in most cases achieved either by modifying actin, or indirectly via activation of key regulators controlling actin dynamics such as Rho-GTPases. A novel group of bacterial virulence factors termed the WXXXE family has emerged as guanine nucleotide exchange factors (GEFs) for these GTPases. The precise mechanism of nucleotide exchange, however, has remained unclear. Here we report the structure of the WXXXE-protein IpgB2 from Shigella flexneri and its complex with human RhoA. We unambiguously identify IpgB2 as a bacterial RhoA-GEF and dissect the molecular mechanism of GDP release, an essential prerequisite for GTP binding. Our observations uncover that IpgB2 induces conformational changes on RhoA mimicking DbI- but not DOCK family GEFs. We also show that dissociation of the GDP.Mg(2+) complex is preceded by the displacement of the metal ion to the alpha-phosphate of the nucleotide, diminishing its affinity to the GTPase. These data refine our understanding of the mode of action not only of WXXXE GEFs but also of mammalian GEFs of the DH/PH family.en
dc.language.isoenen
dc.subject.meshCloning, Molecularen
dc.subject.meshCytoskeletonen
dc.subject.meshGuanine Nucleotide Exchange Factorsen
dc.subject.meshGuanosine Diphosphateen
dc.subject.meshGuanosine Triphosphateen
dc.subject.meshHumansen
dc.subject.meshIonsen
dc.subject.meshMagnesiumen
dc.subject.meshMetalsen
dc.subject.meshNucleotidesen
dc.subject.meshProtein Bindingen
dc.subject.meshProtein Conformationen
dc.subject.meshShigella flexnerien
dc.subject.meshrac1 GTP-Binding Proteinen
dc.subject.meshrhoA GTP-Binding Proteinen
dc.titleStructure of Shigella IpgB2 in complex with human RhoA: implications for the mechanism of bacterial guanine nucleotide exchange factor mimicry.en
dc.typeArticleen
dc.contributor.departmentDivision of Structural Biology, Helmholtz Zentrum für Infektionsforschung, D-38124 Braunschweig, Germany.en
dc.identifier.journalThe Journal of biological chemistryen

Related articles on PubMed

This item is licensed under a Creative Commons License
Creative Commons
All Items in HZI are protected by copyright, with all rights reserved, unless otherwise indicated.