6o3o
From Proteopedia
Structure of human DNAM-1 (CD226) bound to nectin-like protein-5 (necl-5)
Structural highlights
FunctionCD226_HUMAN Involved in intercellular adhesion, lymphocyte signaling, cytotoxicity and lymphokine secretion mediated by cytotoxic T-lymphocyte (CTL) and NK cell (PubMed:8673704). Cell surface receptor for NECTIN2. Upon ligand binding, stimulates T-cell proliferation and cytokine production, including that of IL2, IL5, IL10, IL13, and IFNG. Competes with PVRIG for NECTIN2-binding (PubMed:26755705).[1] [2] Publication Abstract from PubMedNectin 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 A 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. Structural basis for the recognition of nectin-like protein-5 by the human activating immune receptor, DNAM-1.,Deuss FA, Watson GM, Goodall KJ, Leece I, Chatterjee S, Fu Z, Thaysen-Andersen M, Andrews DM, Rossjohn J, Berry R J Biol Chem. 2019 Jun 28. pii: RA119.009261. doi: 10.1074/jbc.RA119.009261. PMID:31253644[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|