Structural Mechanisms of Semaphorin/Plexin Signaling

dc.contributor.advisorRice, Luke M.en
dc.contributor.committeeMemberRosen, Michael K.en
dc.contributor.committeeMemberYu, Hongtaoen
dc.contributor.committeeMemberZhang, Xuewuen
dc.creatorWang, Yuxiaoen 2014
dc.description.abstractPlexins are cell surface receptors that bind to their ligand semaphorins and transduce signals for regulating processes including neuronal development, angiogenesis and immune response. Deregulations of the plexin pathway are associated with cancers and neurodegenerative diseases. Signaling through plexins has been proposed to rely on their GTPase activating protein (GAP) activity for R-Ras and M-Ras. Activation of this GAP activity requires binding of semaphorin to the plexin extracellular region. However, the GAP activity of plexins eluded detection in several studies, and the mechanisms by which semaphorins activate plexins remained elusive. I discovered that plexins function as GAPs specific for Rap GTPases but not for R-Ras or M-Ras. The RapGAP activity of plexins is stimulated by binding of semaphorins, and is essential for the physiological functions of plexins. I further showed that induced-dimerization of plexin cytoplasmic region leads to activation of the GAP domain. The crystal structure of the active dimer of PlexinC1 was determined, revealing the structural basis for the dimerization-induced allosteric activation of plexins. I also solved a structure of PlexinA4 cytoplasmic region, which suggested the existence of a pre-formed inhibitory dimer. Biochemical and cellular assay showed that although PlexinA4 indeed homodimerizes on cell surface, the pre-formed dimer I crystallized is likely to be physiologically irrelevant. To summarize, these findings define an essential pathway for semaphorin-plexin signaling, and reveal the structural mechanisms for the activation of plexins by semaphorins. We also show that plexins in cells exist as pre-formed dimers, the formation of which likely maintains the autoinhibited state of plexins.en
dc.subjectCell Adhesion Moleculesen
dc.subjectNerve Tissue Proteinsen
dc.subjectrap GTP-Binding Proteinsen
dc.titleStructural Mechanisms of Semaphorin/Plexin Signalingen
dc.type.materialtexten School of Biomedical Sciencesen Biophysicsen Southwestern Medical Centeren of Philosophyen


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