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Structural Principles in Robo Activation and Auto-inhibition.

Reut Barak1, Galit Yom-Tov1, Julia Guez-Haddad1

  • 1The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Israel.

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|March 12, 2019
PubMed
Summary

The Roundabout (Robo) receptor

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Structural Biology

Background:

  • Neuronal development relies on precise cell guidance.
  • The Roundabout (Robo) receptor family and Slit ligands mediate this process.
  • The precise activation mechanism of Robo receptors remains largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanism of Robo receptor activation.
  • To determine the structural basis for Robo receptor auto-inhibition and activation.

Main Methods:

  • X-ray crystallography of the human Robo2 ectodomain.
  • Functional assays in mouse primary neurons and C. elegans.
  • Analysis of conserved Robo dimerization across species.

Main Results:

  • A 3.6 Å crystal structure of the intact human Robo2 ectodomain was determined.
  • Robo cis dimerization via the D4 domain is conserved and essential for function.
  • Two auto-inhibitory mechanisms were identified: cis blocking and trans interactions.
  • Slit stimulation appears to release this auto-inhibition, enabling dimerization and activation.

Conclusions:

  • The study reveals a novel auto-inhibition mechanism for Robo receptors.
  • This mechanism involves both cis and trans interactions, preventing premature activation.
  • Slit binding likely triggers the release of auto-inhibition, leading to receptor activation and downstream signaling.