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Structural Basis for Plexin Activation and Regulation.

Youxin Kong1, Bert J C Janssen1, Tomas Malinauskas1

  • 1Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Neuron
|July 12, 2016
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Summary
This summary is machine-generated.

Class A plexins (PlxnAs) are receptors controlling nervous system development. Their extracellular domains maintain an autoinhibitory state, preventing premature signaling and ensuring proper axon guidance.

Keywords:
autoinhibitionaxon guidancesemaphorin signalingstructure-function

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Structural Biology

Background:

  • Class A plexins (PlxnAs) function as semaphorin receptors crucial for nervous system development and plasticity.
  • While PlxnA signaling relies on cytoplasmic domain dimerization, the extracellular regulation and activation mechanisms are not well understood.

Purpose of the Study:

  • To elucidate the structural basis of extracellular regulation and activation mechanisms of Class A plexins.
  • To investigate the autoinhibitory mechanisms governing PlxnA ectodomains.

Main Methods:

  • X-ray crystallography to determine the structures of full ectodomains of PlxnA1, PlxnA2, and PlxnA4.
  • Biophysical assays, live cell fluorescence microscopy, and cell-based neuronal growth cone collapse assays to confirm structural findings.

Main Results:

  • Crystal structures reveal a ring-like conformation of PlxnA ectodomains (domains 1-9) with domain 10 extending outwards.
  • All structures exhibit autoinhibitory, intermolecular "head-to-stalk" interactions between domain 1 and domains 4-5.
  • These interactions were validated through various biophysical and cell-based assays.

Conclusions:

  • PlxnA ectodomains play a dual role: maintaining autoinhibitory separation of cytoplasmic domains via "head-to-stalk" interactions and facilitating ligand-induced activation.
  • A novel molecular mechanism preventing premature activation of axon guidance receptors has been identified.