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

Journal article

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.

Authors: Deuss, FA; Watson, GM; Goodall, KJ; Leece, I; Chatterjee, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Journal of Biological Chemistry
• Volume: 294
• Issue: 33
• Pages: 12534-12546
• Publication date: 2019-06-28
• DOI: 10.1074/jbc.ra119.009261
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Immunology; Immune receptor; Receptor; Immunoglobulin domain; Immune system; Biology; Cell biology; Cell adhesion molecule; Immunoglobulin superfamily; Cell; Nectin; Biochemistry; Cell adhesion; Effector