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

Felix A Deuss, Gabrielle M Watson, Katharine J Goodall, Isobel Leece, Sayantani Chatterjee, Zhihui Fu, Morten Thaysen-Andersen, Daniel M Andrews, Jamie Rossjohn, Richard Berry

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)12534-12546
Number of pages13
JournalThe Journal of Biological Chemistry
Volume294
Issue number33
DOIs
Publication statusPublished - 16 Aug 2019

Keywords

  • DNAX accessory molecule-1 (DNAM-1)
  • cancer immunotherapy
  • CD226 molecule
  • nectin-like protein-5 (NECL-5)
  • PVR cell adhesion molecule
  • protein structure
  • immunology
  • immunoglobulin fold
  • cell adhesion
  • natural killer cells (NK cells)

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