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A Dual Binding Mode for RhoGTPases in Plexin Signalling.

DOI: 10.1371/journal.pbio.1001134 DOI Help
PMID: 21912513 PMID Help

Authors: Christian H. Bell (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom) , Edith Jones (University of Oxford) , Christian Siebold (Wellcome Trust Centre for Human Genetics, University of Oxford) , A Radu Aricescu (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos Biology , VOL 9 (8)

State: Published (Approved)
Published: December 2011

Open Access Open Access

Abstract: Plexins are cell surface receptors for the semaphorin family of cell guidance cues. The cytoplasmic region comprises a Ras GTPase-activating protein (GAP) domain and a RhoGTPase binding domain. Concomitant binding of extracellular semaphorin and intracellular RhoGTPase triggers GAP activity and signal transduction. The mechanism of this intricate regulation remains elusive. We present two crystal structures of the human Plexin-B1 cytoplasmic region in complex with a constitutively active RhoGTPase, Rac1. The structure of truncated Plexin-B1-Rac1 complex provides no mechanism for coupling RhoGTPase and Ras binding sites. On inclusion of the juxtamembrane helix, a trimeric structure of Plexin-B1-Rac1 complexes is stabilised by a second, novel, RhoGTPase binding site adjacent to the Ras site. Site-directed mutagenesis combined with cellular and biophysical assays demonstrate that this new binding site is essential for signalling. Our findings are consistent with a model in which extracellular and intracellular plexin clustering events combine into a single signalling output.

Journal Keywords: Crystallography ; X-Ray ; Cytoplasm ; HEK293; Humans ; Intracellular; Models ; Biological ; Models ; Molecular ; Nerve; Protein; Secondary ; Protein; Tertiary ; Receptors ; Cell; Signal; rac1 GTP-Binding Protein

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF