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Structural basis for the recognition of nectin-like protein-5 by the human-activating immune receptor, DNAM-1
| Content Provider | Scilit |
|---|---|
| Author | Deuss, Felix A. Watson, Gabrielle M. Goodall, Katharine J. Leece, Isobel Chatterjee, Sayantani Fu, Zhihui Thaysen-Andersen, Morten Andrews, Daniel M. Rossjohn, Jamie Berry, Richard |
| Copyright Year | 2019 |
| Description | Journal: Journal of Biological Chemistry 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. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699837/pdf http://www.jbc.org/content/294/33/12534.full.pdf |
| Ending Page | 12546 |
| Page Count | 13 |
| Starting Page | 12534 |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| DOI | 10.1074/jbc.ra119.009261 |
| Journal | Journal of Biological Chemistry |
| Issue Number | 33 |
| Volume Number | 294 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2019-08-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Journal of Biological Chemistry Biochemistry and Molecular Biology Cd226 Molecule Dnax Accessory Molecule-1 (dnam-1) Pvr Cell Adhesion Molecule Cancer Immunotherapy Cell Adhesion Immunoglobulin Fold Natural Killer Cells (nk Cells) Nectin-like Protein-5 (necl-5) Protein Structure |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
