4dfi

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Crystal structure of cell adhesion molecule nectin-2/CD112 mutant FAMP

Structural highlights

4dfi is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.8Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NECT2_HUMAN Modulator of T-cell signaling. Can be either a costimulator of T-cell function, or a coinhibitor, depending on the receptor it binds to. Upon binding to CD226, stimulates T-cell proliferation and cytokine production, including that of IL2, IL5, IL10, IL13, and IFNG. Upon interaction with PVRIG, inhibits T-cell proliferation. These interactions are competitive (PubMed:26755705). Probable cell adhesion protein (PubMed:9657005).[1] [2] (Microbial infection) Acts as a receptor for herpes simplex virus 1 (HHV-1) mutant Rid1, herpes simplex virus 1 (HHV-2) and pseudorabies virus (PRV).[3] [4]

Publication Abstract from PubMed

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-A 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.

Crystal Structure of Cell Adhesion Molecule Nectin-2/CD112 and Its Binding to Immune Receptor DNAM-1/CD226.,Liu J, Qian X, Chen Z, Xu X, Gao F, Zhang S, Zhang R, Qi J, Gao GF, Yan J J Immunol. 2012 Jun 1;188(11):5511-20. Epub 2012 Apr 30. PMID:22547693[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Zhu Y, Paniccia A, Schulick AC, Chen W, Koenig MR, Byers JT, Yao S, Bevers S, Edil BH. Identification of CD112R as a novel checkpoint for human T cells. J Exp Med. 2016 Feb 8;213(2):167-76. doi: 10.1084/jem.20150785. Epub 2016 Jan 11. PMID:26755705 doi:http://dx.doi.org/10.1084/jem.20150785
  2. ↑ Warner MS, Geraghty RJ, Martinez WM, Montgomery RI, Whitbeck JC, Xu R, Eisenberg RJ, Cohen GH, Spear PG. A cell surface protein with herpesvirus entry activity (HveB) confers susceptibility to infection by mutants of herpes simplex virus type 1, herpes simplex virus type 2, and pseudorabies virus. Virology. 1998 Jun 20;246(1):179-89. PMID:9657005 doi:http://dx.doi.org/10.1006/viro.1998.9218
  3. ↑ Martinez WM, Spear PG. Structural features of nectin-2 (HveB) required for herpes simplex virus entry. J Virol. 2001 Nov;75(22):11185-95. PMID:11602758 doi:http://dx.doi.org/10.1128/JVI.75.22.11185-11195.2001
  4. ↑ Warner MS, Geraghty RJ, Martinez WM, Montgomery RI, Whitbeck JC, Xu R, Eisenberg RJ, Cohen GH, Spear PG. A cell surface protein with herpesvirus entry activity (HveB) confers susceptibility to infection by mutants of herpes simplex virus type 1, herpes simplex virus type 2, and pseudorabies virus. Virology. 1998 Jun 20;246(1):179-89. PMID:9657005 doi:http://dx.doi.org/10.1006/viro.1998.9218
  5. ↑ Liu J, Qian X, Chen Z, Xu X, Gao F, Zhang S, Zhang R, Qi J, Gao GF, Yan J. Crystal Structure of Cell Adhesion Molecule Nectin-2/CD112 and Its Binding to Immune Receptor DNAM-1/CD226. J Immunol. 2012 Jun 1;188(11):5511-20. Epub 2012 Apr 30. PMID:22547693 doi:10.4049/jimmunol.1200324

Contents


PDB ID 4dfi

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