4DFH

Crystal structure of cell adhesion molecule nectin-2/CD112 variable domain

Summary for 4DFH

• Entry DOI: 10.2210/pdb4dfh/pdb
• Related: 4DFI
• Descriptor: Poliovirus receptor-related protein 2 (2 entities in total)
• Functional Keywords: cell adhesion, dnam-1, cell surface
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: Q92692
• Total number of polymer chains: 2
• Total formula weight: 27901.56

Authors

Liu, J.,Qian, X.,Chen, Z.,Xu, X.,Gao, F.,Zhang, S.,Zhang, R.,Qi, J.,Gao, G.F.,Yan, J. (deposition date: 2012-01-23, release date: 2012-06-06)

Primary citation

Liu, J.,Qian, X.,Chen, Z.,Xu, X.,Gao, F.,Zhang, S.,Zhang, R.,Qi, J.,Gao, G.F.,Yan, J.
Crystal Structure of Cell Adhesion Molecule Nectin-2/CD112 and Its Binding to Immune Receptor DNAM-1/CD226
J.Immunol., 188:5511-5520, 2012

PubMed Abstract: The nectin and nectin-like molecule (Necl) family includes important cell adhesion molecules (CAMs) characterized by their Ig-like nature. Such CAMs regulate a broad spectrum of cell-cell interactions, including the interaction between NK cells and cytotoxic T lymphocytes (CTLs) and their target cells. CAM members nectin-2 (CD112) and Necl-5 (CD155) are believed to form homodimers (for nectin-2) or heterodimers in their functions for cell adhesion, as well as to interact with immune costimulatory receptor DNAX accessory molecule 1 (DNAM-1) (CD226) to regulate functions of both NK and CTL cells. However, the structural basis of the interactive mode of DNAM-1 with nectin-2 or Necl-5 is not yet understood. In this study, a soluble nectin-2 Ig-like V-set domain (nectin-2v) was successfully prepared and demonstrated to bind to both soluble ectodomain and cell surface-expressed full-length DNAM-1. The 1.85-Å crystal structure of nectin-2v displays a perpendicular homodimer arrangement, revealing the homodimer characteristics of the nectin and Necls. Further mutational analysis indicated that disruption of the homodimeric interface of nectin-2v led to a failure of the homodimer formation, as confirmed by crystal structure and biochemical properties of the mutant protein of nectin-2v. Interestingly, the monomer mutant also loses DNAM-1 binding, as evidenced by cell staining with tetramers and surface plasmon resonance assays. The data indicate that interaction with DNAM-1 requires either the homodimerization or engagement of the homodimeric interface of nectin-2v. These results have implications for immune intervention of tumors or autoimmune diseases in the DNAM-1/nectin-2-dependent pathway.

PubMed: 22547693
DOI: 10.4049/jimmunol.1200324

Experimental method

X-RAY DIFFRACTION (1.85 Å)