Journal Article

DZNE-2020-05061

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural Basis for Plexin Activation and Regulation.

Kong, Y. ; Janssen, B. J. C. ; Malinauskas, T. ; Vangoor, V. R. ; Coles, C. H.DZNE* ; Kaufmann, R. ; Ni, T. ; Gilbert, R. J. C. ; Padilla-Parra, S. ; Pasterkamp, R. J. (Corresponding author) ; Jones, E. Y.

2016
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.neuron.2016.06.018

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.

Keyword(s): Animals (MeSH) ; Mice (MeSH) ; Models, Molecular (MeSH) ; Nerve Tissue Proteins: chemistry (MeSH) ; Nerve Tissue Proteins: metabolism (MeSH) ; Nerve Tissue Proteins: ultrastructure (MeSH) ; Protein Multimerization (MeSH) ; Receptors, Cell Surface: chemistry (MeSH) ; Receptors, Cell Surface: metabolism (MeSH) ; Receptors, Cell Surface: ultrastructure (MeSH) ; Structure-Activity Relationship (MeSH) ; Nerve Tissue Proteins ; Plxna1 protein, mouse ; Plxna2 protein, mouse ; Plxna4 protein, mouse ; Receptors, Cell Surface

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Contributing Institute(s):

1. Axon Growth and Regeneration (AG Bradke)

Research Program(s):

1. 341 - Molecular Signaling (POF3-341) (POF3-341)

Appears in the scientific report 2016

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