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Structural basis for plexin activation and regulation

DOI: 10.1016/j.neuron.2016.06.018 DOI Help

Authors: Youxin Kong (University of Oxford) , Bert J. C. Janssen (University of Oxford) , Tomas Malinauskas (University of Oxford) , Vamshidhar r. Vangoor (University Medical Center Utrecht) , Charlotte Coles (Wellcome Trust Centre for Human Genetics, University of Oxford) , Rainer Kaufmann (University of Oxford) , Tao Ni (Wellcome Trust Centre for Human Genetics, University of Oxford) , Robert J. C. Gilbert (Wellcome Trust Centre for Human Genetics, University of Oxford) , Sergi Padilla-Parra (Wellcome Trust Centre for Human Genetics, University of Oxford) , R. jeroen Pasterkamp (University Medical Center Utrecht) , E. yvonne Jones (Wellcome Trust Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Neuron , VOL 91 , PAGES 548 - 560

State: Published (Approved)
Published: August 2016
Diamond Proposal Number(s): 8423 , 10627

Open Access Open Access

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.

Journal Keywords: semaphorin signaling; axon guidance; autoinhibition; structure-function

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: ID23-2 at ESRF

Added On: 29/09/2016 22:35


Discipline Tags:

Health & Wellbeing Neurology Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)