title: Crystal structure of the extracellular juxtamembrane region of Robo1.
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.
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
authors.forename: Reut
authors.initials: R
authors.lastname: Barak
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel; Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 5290002, Israel.
authors.forename: Roxane
authors.initials: R
authors.lastname: Lahmi
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
authors.forename: Lada
authors.initials: L
authors.lastname: Gevorkyan-Airapetov
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
authors.forename: Eliad
authors.initials: E
authors.lastname: Levy
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel; Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 5290002, Israel.
authors.forename: Amit
authors.initials: A
authors.lastname: Tzur
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel. Electronic address: yarden.opatowsky@biu.ac.il.
authors.forename: Yarden
authors.initials: Y
authors.lastname: Opatowsky
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D004591:Electrophoresis, Polyacrylamide Gel; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D000097905:Roundabout Proteins
chemical_list: D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins
keywords: Receptor; Robo1; Shedding; Slit; Structure; X-ray crystallography