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PMID: 17848514 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Structural insights into the Slit-Robo complex.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 104 ·No. 38 ·2007-09-18 ·Pages 14923-8

Morlot C, Thielens NM, Ravelli RB, Hemrika W, Romijn RA, Gros P, Cusack S, McCarthy AA

Abstract

Slits are large multidomain leucine-rich repeat (LRR)-containing proteins that provide crucial guidance cues in neuronal and vascular development. More recently, Slits have been implicated in heart morphogenesis, angiogenesis, and tumor metastasis. Slits are ligands for the Robo (Roundabout) receptors, which belong to the Ig superfamily of transmembrane signaling molecules. The Slit-Robo interaction is mediated by the second LRR domain of Slit and the two N-terminal Ig domains of Robo, but the molecular details of this interaction and how it induces signaling remain unclear. Here we describe the crystal structures of the second LRR domain of human Slit2 (Slit2 D2), the first two Ig domains of its receptor Robo1 (Ig1-2), and the minimal complex between these proteins (Slit2 D2-Robo1 Ig1). Slit2 D2 binds with its concave surface to the side of Ig1 with electrostatic and hydrophobic contact regions mediated by residues that are conserved in other family members. Surface plasmon resonance experiments and a mutational analysis of the interface confirm that Ig1 is the primary domain for binding Slit2. These structures provide molecular insight into Slit-Robo complex formation and will be important for the development of novel cancer therapeutics.

MeSH Terms
Amino Acid Sequence Binding Sites Crystallography, X-Ray Heparin/metabolism Humans Intercellular Signaling Peptides and Proteins/chemistry,metabolism Models, Biological Models, Molecular Molecular Sequence Data Mutagenesis Nerve Tissue Proteins/chemistry,metabolism Protein Structure, Tertiary Receptors, Immunologic/chemistry,metabolism Recombinant Proteins/chemistry,genetics,metabolism Signal Transduction Structure-Activity Relationship Surface Plasmon Resonance
Chemicals
Intercellular Signaling Peptides and Proteins Nerve Tissue Proteins Receptors, Immunologic Recombinant Proteins roundabout protein Heparin Slit homolog 2 protein
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Morlot Cecile
European Molecular Biology Laboratory, 6 Rue Jules Horowitz, BP 181, 38042 Grenoble, France.
Thielens Nicole M
Ravelli Raimond B G
Hemrika Wieger
Romijn Roland A
Gros Piet
Cusack Stephen
McCarthy Andrew A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0705310104
Published
2007-09-18
Epub
2007-00-11
Pages
14923-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1975871
Subset
IM
Databases
PDB
2V9Q, 2V9R, 2V9S, 2V9T
External Links
PubMed source DOI: 10.1073/pnas.0705310104 PMC Full Text View journal details
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