Structure and functional relevance of the Slit2 homodimerization domain

EMBO Rep. 2009 Jul;10(7):736-41. doi: 10.1038/embor.2009.95. Epub 2009 Jun 5.

Abstract

Slit proteins are secreted ligands that interact with the Roundabout (Robo) receptors to provide important guidance cues in neuronal and vascular development. Slit-Robo signalling is mediated by an interaction between the second Slit domain and the first Robo domain, as well as being dependent on heparan sulphate. In an effort to understand the role of the other Slit domains in signalling, we determined the crystal structure of the fourth Slit2 domain (D4) and examined the effects of various Slit2 constructs on chick retinal ganglion cell axons. Slit2 D4 forms a homodimer using the conserved residues on its concave face, and can also bind to heparan sulphate. We observed that Slit2 D4 frequently results in growth cones with collapsed lamellipodia and that this effect can be inhibited by exogenously added heparan sulphate. Our results show that Slit2 D4-heparan sulphate binding contributes to a Slit-Robo signalling mechanism more intricate than previously thought.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Conserved Sequence
  • Decorin
  • Extracellular Matrix Proteins / chemistry
  • Heparitin Sulfate / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / chemistry*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Models, Molecular
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / metabolism*
  • Protein Multimerization*
  • Protein Structure, Tertiary
  • Proteoglycans / chemistry
  • Sequence Homology, Amino Acid
  • Static Electricity
  • Structure-Activity Relationship

Substances

  • DCN protein, human
  • Decorin
  • Extracellular Matrix Proteins
  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Proteoglycans
  • Heparitin Sulfate
  • Slit homolog 2 protein

Associated data

  • PDB/2WFH