Contactin 2 homophilic adhesion structure and conformational plasticity

Area of Science:

• Neuroscience
• Structural Biology
• Biochemistry

Background:

• Contactin 2 is a cell-surface glycoprotein crucial for nervous system development.
• It mediates homotypic cell-cell interactions, influencing cell guidance, differentiation, and adhesion.
• The protein comprises six immunoglobulin (Ig) and four fibronectin type III (FnIII) domains, with the N-terminal Ig domains forming a horseshoe structure involved in dimerization.

Purpose of the Study:

• To determine the crystal structure of the six-domain contactin 2 ectodomain (contactin 2^Ig1-6).
• To elucidate the mechanisms of contactin 2 oligomerization and its role in cell adhesion.
• To investigate the structural basis for contactin 2's function in diverse intercellular environments.

Main Methods:

• X-ray crystallography for high-resolution structure determination.
• Size exclusion chromatography with multi-angle light scattering (SEC-MALS).
• Small-angle X-ray scattering (SAXS) and native mass spectrometry (MS).
• Negative-stain electron microscopy.

Main Results:

• The crystal structure reveals the Ig5-Ig6 domains are oriented away from the Ig1-4 horseshoe structure, with flexible interdomain connections.
• Contactin 2^Ig1-6 exhibits two distinct dimer states (via Ig1-Ig2 and Ig3-Ig6 interactions), facilitating the formation of larger oligomers.
• Oligomerization is dependent on glycosylation, and the full ectodomain displays inherent plasticity.
• Intermolecular binding sites and ectodomain plasticity explain its function as a homotypic adhesion molecule.

Conclusions:

• The structural flexibility and distinct binding modes of contactin 2 are key to its oligomerization.
• Glycan-dependent oligomerization and inherent plasticity enable contactin 2 to mediate cell adhesion in various neural contexts.
• This study provides a structural basis for understanding contactin 2's function in neural development and organization.