title: Structural Basis for Plexin Activation and Regulation.
abstract: Class A plexins (PlxnAs) act as semaphorin receptors and control diverse aspects of nervous system development and plasticity, ranging from axon guidance and neuron migration to synaptic organization. PlxnA signaling requires cytoplasmic domain dimerization, but extracellular regulation and activation mechanisms remain unclear. Here we present crystal structures of PlxnA (PlxnA1, PlxnA2, and PlxnA4) full ectodomains. Domains 1-9 form a ring-like conformation from which the C-terminal domain 10 points away. All our PlxnA ectodomain structures show autoinhibitory, intermolecular "head-to-stalk" (domain 1 to domain 4-5) interactions, which are confirmed by biophysical assays, live cell fluorescence microscopy, and cell-based and neuronal growth cone collapse assays. This work reveals a 2-fold role of the PlxnA ectodomains: imposing a pre-signaling autoinhibitory separation for the cytoplasmic domains via intermolecular head-to-stalk interactions and supporting dimerization-based PlxnA activation upon ligand binding. More generally, our data identify a novel molecular mechanism for preventing premature activation of axon guidance receptors.
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Youxin
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Bert J C
authors.initials: BJ
authors.lastname: Janssen
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Tomas
authors.initials: T
authors.lastname: Malinauskas
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Vamshidhar R
authors.initials: VR
authors.lastname: Vangoor
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Coles
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kaufmann
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Tao
authors.initials: T
authors.lastname: Ni
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Robert J C
authors.initials: RJ
authors.lastname: Gilbert
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Sergi
authors.initials: S
authors.lastname: Padilla-Parra
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: r.j.pasterkamp@umcutrecht.nl.
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. Electronic address: yvonne@strubi.ox.ac.uk.
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
mesh_terms: D000818:Animals; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D055503:Protein Multimerization; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D013329:Structure-Activity Relationship
chemical_list: D009419:Nerve Tissue Proteins; C492114:Plxna1 protein, mouse; C492113:Plxna2 protein, mouse; C492110:Plxna4 protein, mouse; D011956:Receptors, Cell Surface
keywords: autoinhibition; axon guidance; semaphorin signaling; structure-function