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

Structure (London, England : 1993) 2024 Jan 04

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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 2Ig1-6 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 2Ig1-6 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. Copyright © 2023 Elsevier Ltd. All rights reserved.

Citation

Lucas M P Chataigner, Lena Thärichen, J Wouter Beugelink, Joke C M Granneman, Nadia J Mokiem, Joost Snijder, Friedrich Förster, Bert J C Janssen. Contactin 2 homophilic adhesion structure and conformational plasticity. Structure (London, England : 1993). 2024 Jan 04;32(1):60-73.e5