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Structural basis for the recognition of nectin-like protein-5 by the human-activating immune receptor, DNAM-1

Deuss, Felix A., Watson, Gabrielle M., Goodall, Katharine J., Leece, Isobel, Chatterjee, Sayantani, Fu, Zhihui, Thaysen-Andersen, Morten, Andrews, Daniel M., Rossjohn, Jamie and Berry, Richard 2019. Structural basis for the recognition of nectin-like protein-5 by the human-activating immune receptor, DNAM-1. Journal of Biological Chemistry 294 (33) , pp. 12534-12546. 10.1074/jbc.RA119.009261

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Nectin and nectin-like (Necl) adhesion molecules are broadly overexpressed in a wide range of cancers. By binding to these adhesion molecules, the immunoreceptors DNAX accessory molecule-1 (DNAM-1), CD96 molecule (CD96), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) play a crucial role in regulating the anticancer activities of immune effector cells. However, within this axis, it remains unclear how DNAM-1 recognizes its cognate ligands. Here, we determined the structure of human DNAM-1 in complex with nectin-like protein-5 (Necl-5) at 2.8 Å resolution. Unexpectedly, we found that the two extracellular domains (D1–D2) of DNAM-1 adopt an unconventional “collapsed” arrangement that is markedly distinct from those in other immunoglobulin-based immunoreceptors. The DNAM-1/Necl-5 interaction was underpinned by conserved lock–and–key motifs located within their respective D1 domains, but also included a distinct interface derived from DNAM-1 D2. Mutation of the signature DNAM-1 “key” motif within the D1 domain attenuated Necl-5 binding and natural killer cell–mediated cytotoxicity. Altogether, our results have implications for understanding the binding mode of an immune receptor family that is emerging as a viable candidate for cancer immunotherapy.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Date of First Compliant Deposit: 23 September 2019
Date of Acceptance: 28 June 2019
Last Modified: 20 Jun 2020 02:05

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