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Structure of the heterophilic interaction between the nectin-like 4 and nectin-like 1 molecules.

Liu X1,2, An T1, Li D1, Fan Z3, Xiang P1, Li C1, Ju W1, Li J1, Hu G1, Qin B4, Yin B1, Wojdyla JA5, Wang M5, Yuan J1, Qiang B1, Shu P6, Cui S7, Peng X6,2


Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2068-2077.

PMID: 30674679


Abstract

Nectin-like (Necl) molecules are Ca2+-independent Ig-like transmembrane cell adhesion molecules that participate in junctions between different cell types. The specific cell-cell adhesions mediated by Necl proteins are important in neural development and have been implicated in neurodegenerative diseases. Here, we present the crystal structure of the mouse Necl-4 full ectodomain and the structure of the heterophilic Necl ectodomain complex formed by the mNecl-4 and mNecl-1 ectodomains. We demonstrate that, while the ectodomain of mNecl-4 is monomeric, it forms a stable heterodimer with Ig1 of mNecl-1, with an affinity significantly higher than that observed for self-dimerization of the mNecl-1 ectodomain. We validated our structural characterizations by performing a surface plasmon resonance assay and an Fc fusion protein binding assay in mouse primary dorsal root ganglia neurites and Schwann cells and identified a selection of residues important for heterophilic interactions. Finally, we proposed a model of Necl binding specificity that involves an induced-fit conformational change at the dimerization interface.