Recognition of nectin-2 by the natural killer cell receptor T cell immunoglobulin and ITIM domain (TIGIT)
Recognition of nectin-2 by the natural killer cell receptor T cell immunoglobulin and ITIM domain (TIGIT)
复制标题
DOI：
10.1074/jbc.m117.786483
复制
发表时间：
2017-07-07
影响因子：
4.8
通讯作者：
Berry, Richard
中科院分区：
文献类型：
--
作者：
Deuss, Felix A.;Gully, Benjamin S.;Berry, Richard
T细胞免疫球蛋白和ITIM结构域(TIGIT)是一种表达于自然杀伤细胞(NK)表面的抑制性受体。TIGIT识别Nextin和Nextin样黏附分子，因此在针对恶性转化的先天免疫反应中发挥关键作用。尽管TIGIT Nectin样蛋白-5(Necl-5)的相互作用已被熟知，但TIGIT如何与Nectin-2结合仍不清楚，Nectin-2是一种在乳腺癌和卵巢癌中广泛过度表达的受体。在这里，我们发现TIGIT与Nectin-2的免疫球蛋白结构域结合，该结构域离膜最远，亲和力为6µM，略低于TIGIT/Necl-5相互作用的亲和力(3.2µM)。TIGIT/Nectin-2结合破坏了预先组装的Nectin-2寡聚体，表明受体-配体和配体-配体的结合是相互排斥的事件。事实上，TIGIT与Nectin-2的第一个免疫球蛋白结构域结合的晶体结构表明，受体和配体使用相同的分子表面和保守的“Lock and Key”结合基序来介导Nectin/Nectin同型相互作用以及TIGIT/Necl-5的识别。用突变的方法，我们剖析了TIGIT/Nectin-2相互作用的能量基础，发现Nectin-2的“芳香钥匙”对这种相互作用至关重要，而锁的变化是可以容忍的。此外，我们发现配体的C-C‘环决定了TIGIT结合层次。总之，这些发现拓宽了我们对Nectin/Nectin受体相互作用的理解，并对更好地理解自身免疫性疾病和癌症的分子基础具有重要意义。
T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on the surface of natural killer (NK) cells. TIGIT recognizes nectin and nectin-like adhesion molecules and thus plays a critical role in the innate immune response to malignant transformation. Although the TIGIT nectin-like protein-5 (necl-5) interaction is well understood, how TIGIT engages nectin-2, a receptor that is broadly over-expressed in breast and ovarian cancer, remains unknown. Here, we show that TIGIT bound to the immunoglobulin domain of nectin-2 that is most distal from the membrane with an affinity of 6 mu M, which was moderately lower than the affinity observed for the TIGIT/necl-5 interaction (3.2 mu M). The TIGIT/nectin-2 binding disrupted preassembled nectin-2 oligomers, suggesting that receptor-ligand and ligand-ligand associations are mutually exclusive events. Indeed, the crystal structure of TIGIT bound to the first immunoglobulin domain of nectin-2 indicated that the receptor and ligand dock using the same molecular surface and a conserved " lock and key" binding motifs previously observed to mediate nectin/nectin homotypic interactions as well as TIGIT/necl-5 recognition. Using a mutagenesis approach, we dissected the energetic basis for the TIGIT/nectin-2 interaction and revealed that an " aromatic key" of nectin-2 is critical for this interaction, whereas variations in the lock were tolerated. Moreover, we found that the C-C' loop of the ligand dictates the TIGIT binding hierarchy. Altogether, these findings broaden our understanding of nectin/nectin receptor interactions and have implications for better understanding the molecular basis for autoimmune disease and cancer.