Crystal structure of the extracellular juxtamembrane region of Robo1

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

doi:10.1016/j.jsb.2014.02.019

Crystal structure of the extracellular juxtamembrane region of Robo1

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

The Mina and Everard Goodman Faculty of Life Sciences - at Bar-Ilan University

Research output: Contribution to journal › Article › peer-review

18 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 language	English
Pages (from-to)	283-291
Number of pages	9
Journal	Journal of Structural Biology
Volume	186
Issue number	2
DOIs	https://doi.org/10.1016/j.jsb.2014.02.019
State	Published - 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.

Funding

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.

Funders	Funder number
National Institute for Psychobiology	223-11-12
German-Israeli Foundation for Scientific Research and Development	2265/2010
Israel Cancer Association	20120067
Israel Science Foundation	182/10
Israeli Centers for Research Excellence	41/11

Keywords

Receptor
Robo1
Shedding
Slit
Structure
X-ray crystallography

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jsb.2014.02.019

Cite this

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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.",

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author = "Reut Barak and Roxane Lahmi and Lada Gevorkyan-Airapetov and Eliad Levy and Amit Tzur and Yarden Opatowsky",

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{\textquoteright}s BM14, ID14, ID23, and ID29 beamline scientists, and the staff of BESSY II BL14.1. ",

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AU - Tzur, Amit

AU - Opatowsky, Yarden

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AB - 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.

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Crystal structure of the extracellular juxtamembrane region of Robo1

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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