Structural bases for CRMP function in plexin-dependent semaphorin3A signaling

Rahul C. Deo, Eric F. Schmidt, Abdellah Elhabazi, Hideaki Togashi, Stephen K. Burley, Stephen M. Strittmatter

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

Collapsin response mediator proteins (CRMPs) are cytosolic phosphoproteins involved in neuronal differentiation and axonal guidance. CRMP2 was previously shown to mediate the repulsive effect of Sema3A on axons and to participate in axonal specification. The X-ray crystal structure of murine CRMP1 was determined at 2.1 A resolution and demonstrates that CRMP1 is a bilobed 'lung-shaped' protein forming a tetrameric assembly. Structure-based mutagenesis of surface-exposed residues was employed to map functional domains. As a rapid assay for CRMP, we exploited a reconstituted Sema3A signaling system in COS-7 cells expressing the receptor components Neuropilin1 and PlexinA1 (NP1/PlexA1). In these cells, CRMP and PlexA1 form a physical complex that is reduced in amount by NP1 but enhanced by Sema3A/NP1. Furthermore, CRMP accelerates Sema3A-induced cell contraction. Alanine substitutions in one domain of CRMP1 produce a constitutively active protein that causes Sema3A-independent COS-7 contraction. This mutant CRMP mimics the DRG neurite outgrowth-inhibiting effects of Sema3A and reduces Sema3A-induced axonal repulsion. These data provide a structural view of CRMP function in Plex-dependent Sema3A signaling.

Original languageEnglish (US)
Pages (from-to)9-22
Number of pages14
JournalEMBO Journal
Volume23
Issue number1
DOIs
StatePublished - Jan 14 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Molecular Biology
  • Neuroscience(all)

Keywords

  • CRMP
  • Neuropilin
  • Plexin
  • Semaphorin

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