title: Structural basis for activation and non-canonical catalysis of the Rap GTPase activating protein domain of plexin.
abstract: Plexins are cell surface receptors that bind semaphorins and transduce signals for regulating neuronal axon guidance and other processes. Plexin signaling depends on their cytoplasmic GTPase activating protein (GAP) domain, which specifically inactivates the Ras homolog Rap through an ill-defined non-canonical catalytic mechanism. The plexin GAP is activated by semaphorin-induced dimerization, the structural basis for which remained unknown. Here we present the crystal structures of the active dimer of zebrafish PlexinC1 cytoplasmic region in the apo state and in complex with Rap. The structures show that the dimerization induces a large-scale conformational change in plexin, which opens the GAP active site to allow Rap binding. Plexin stabilizes the switch II region of Rap in an unprecedented conformation, bringing Gln63 in Rap into the active site for catalyzing GTP hydrolysis. The structures also explain the unique Rap-specificity of plexins. Mutational analyses support that these mechanisms underlie plexin activation and signaling. DOI:http://dx.doi.org/10.7554/eLife.01279.001.
authors.affiliation: Department of Pharmacology , University of Texas Southwestern Medical Center , Dallas , United States.
authors.forename: Yuxiao
authors.initials: Y
authors.lastname: Wang
authors.forename: Heath G
authors.initials: HG
authors.lastname: Pascoe
authors.forename: Chad A
authors.initials: CA
authors.lastname: Brautigam
authors.forename: Huawei
authors.initials: H
authors.lastname: He
authors.forename: Xuewu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015027:Zebrafish / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020668:rap GTP-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D009419:Nerve Tissue Proteins; D029961:Zebrafish Proteins; C091529:plexin; D006160:Guanosine Triphosphate; D020668:rap GTP-Binding Proteins
keywords: GAP; Human; Mouse; Rap; Zebrafish; axon guidance; dimerization; plexin; signal transduction