Crystal structure of the extracellular juxtamembrane region of Robo1

Reut Barak, Roxane Lahmi, Lada Gevorkyan-Airapetov, Eliad Levy, Amit Tzur, Yarden Opatowsky

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Robo receptors play pivotal roles in neurodevelopment, and their deregulation is implicated in several neuropathological conditions and cancers. To date, the mechanism of Robo activation and regulation remains obscure. Here we present the crystal structure of the juxtamembrane (JM) domains of human Robo1. The structure exhibits unexpectedly high backbone similarity to the netrin and RGM binding region of neogenin and DCC, which are functionally related receptors of Robo1. Comparison of these structures reveals a conserved surface that overlaps with a cluster of oncogenic and neuropathological mutations found in all Robo isoforms. The structure also reveals the intricate folding of the JM linker, which points to its role in Robo1 activation. Further experiments with cultured cells demonstrate that exposure or relief of the folded JM linker results in enhanced shedding of the Robo1 ectodomain.

Original languageEnglish
Pages (from-to)283-291
Number of pages9
JournalJournal of Structural Biology
Volume186
Issue number2
DOIs
StatePublished - May 2014

Bibliographical note

Funding Information:
We thank T.J. Boggon, M. Dessau, and J.A. Hirsch for the critical reading of the manuscript and for their comments. This work was supported by funds from the Marie Curie International Reintegration Grants PIRG06-GA-2009-256222 (YO) and PIRG-GA-2010-277062 (AT), the Israel Science Foundation Grant No. 182/10 (YO), the German-Israeli Foundation Grant No. 2265/2010 (YO), the National Institute for Psychobiology Grant No. 223-11-12 (YO), the Israeli Centers of Research Excellence (I-CORE) Center No. 41/11 (AT), and the Israel Cancer Association Grant No. 20120067 (AT). We also thank the European Synchrotron Radiation Facility’s BM14, ID14, ID23, and ID29 beamline scientists, and the staff of BESSY II BL14.1.

Keywords

  • Receptor
  • Robo1
  • Shedding
  • Slit
  • Structure
  • X-ray crystallography

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