Structural characterization of the extracellular domain of caSPR2 and insights into its association with the novel ligand contactin1

Eva N. Rubio-Marrero, Gabriele Vincelli, Cy M. Jeffries, Tanvir R. Shaikh, Irene S. Pakos, Fanomezana M. Ranaivoson, Sventja Von Daake, Borries Demeler, Antonella De Jaco, Guy Perkins, Mark H. Ellisman, Jill Trewhella, Davide Comoletti

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Contactin-associated protein-like 2 (CNTNAP2) encodes for CASPR2, a multidomain single transmembrane protein belonging to the neurexin superfamily that has been implicated in a broad range of human phenotypes including autism and language impairment. Using a combination of biophysical techniques, including small angle x-ray scattering, single particle electron microscopy, analytical ultracentrifugation, and biolayer interferometry, we present novel structural and functional data that relate the architecture of the extracellular domain of CASPR2 to a previously unknown ligand, Contactin1 (CNTN1). Structurally, CASPR2 is highly glycosylated and has an overall compact architecture. Functionally, we show that CASPR2 associates with micromolar affinity with CNTN1 but, under the same conditions, it does not interact with any of the other members of the contactin family. Moreover, by using dissociated hippocampal neurons we show that microbeads loaded with CASPR2, but not with a deletion mutant, co-localize with transfected CNTN1, suggesting that CNTN1 is an endogenous ligand for CASPR2. These data provide novel insights into the structure and function of CASPR2, suggesting a complex role of CASPR2 in the nervous system.

Original languageEnglish (US)
Pages (from-to)5788-5802
Number of pages15
JournalJournal of Biological Chemistry
Volume291
Issue number11
DOIs
StatePublished - Mar 11 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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