Contactin 2 homophilic adhesion structure and conformational plasticity

Lucas M P Chataigner; Lena Thärichen; J Wouter Beugelink; Joke C M Granneman; Nadia J Mokiem; Joost Snijder; Friedrich Förster; Bert J C Janssen

doi:10.1016/j.str.2023.10.012

Contactin 2 homophilic adhesion structure and conformational plasticity

Structure. 2024 Jan 4;32(1):60-73.e5. doi: 10.1016/j.str.2023.10.012. Epub 2023 Nov 21.

Authors

Lucas M P Chataigner¹, Lena Thärichen¹, J Wouter Beugelink¹, Joke C M Granneman¹, Nadia J Mokiem², Joost Snijder², Friedrich Förster¹, Bert J C Janssen³

Affiliations

¹ Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Faculty of Science, Utrecht University, Universiteitsweg 99, Utrecht 3584 CG, the Netherlands.
² Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Padualaan 8, Utrecht 3584 CH, the Netherlands.
³ Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Faculty of Science, Utrecht University, Universiteitsweg 99, Utrecht 3584 CG, the Netherlands. Electronic address: b.j.c.janssen@uu.nl.

PMID: 37992710
DOI: 10.1016/j.str.2023.10.012

Abstract

The cell-surface attached glycoprotein contactin 2 is ubiquitously expressed in the nervous system and mediates homotypic cell-cell interactions to organize cell guidance, differentiation, and adhesion. Contactin 2 consists of six Ig and four fibronectin type III domains (FnIII) of which the first four Ig domains form a horseshoe structure important for homodimerization and oligomerization. Here we report the crystal structure of the six-domain contactin 2^Ig1-6 and show that the Ig5-Ig6 combination is oriented away from the horseshoe with flexion in interdomain connections. Two distinct dimer states, through Ig1-Ig2 and Ig3-Ig6 interactions, together allow formation of larger oligomers. Combined size exclusion chromatography with multiangle light scattering (SEC-MALS), small-angle X-ray scattering (SAXS) and native MS analysis indicates contactin 2^Ig1-6 oligomerizes in a glycan dependent manner. SAXS and negative-stain electron microscopy reveals inherent plasticity of the contactin 2 full-ectodomain. The combination of intermolecular binding sites and ectodomain plasticity explains how contactin 2 can function as a homotypic adhesion molecule in diverse intercellular environments.

Keywords: TAG-1; TAX-1; axonin-1; cell adhesion molecule; contactin; glycoprotein; horseshoe; juxtaparanodal; myelin; structure.

MeSH terms

Binding Sites
Cell Adhesion / physiology
Cell Adhesion Molecules, Neuronal* / chemistry
Contactin 2
Molecular Conformation
Scattering, Small Angle
X-Ray Diffraction

Substances

Contactin 2
Cell Adhesion Molecules, Neuronal