Wilker Peter R, Sedy John R, Grigura Vadim, Murphy Theresa L, Murphy Kenneth M
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Int Immunol. 2007 Jun;19(6):763-73. doi: 10.1093/intimm/dxm044. Epub 2007 May 19.
The T cell Ig domain and mucin domain (TIM) proteins form a conserved family of transmembrane cell-surface glycoproteins expressed by a variety of tissues. Each TIM protein contains a single V-type Ig domain, a glycosylated mucin-like domain, a transmembrane domain and a cytoplasmic domain. TIM proteins recognize a diverse array of ligands, including H-ferritin, galectin-9 as well as other TIM family members. In this study, we demonstrate that the Ig domains of murine TIM-1, -3 and -4 display calcium-dependent binding to ligands expressed by murine splenocytes and several non-murine cell lines, indicating non-species-specific ligand recognition. Further, the intrafamilial interaction of various TIM family Ig domains with surface-expressed TIM-1 and TIM-4 requires an intact TIM-1 and TIM-4 glycosylated mucin stalk. Importantly, we also uncovered the previously unrecognized potential for homotypic TIM interactions in forming ligand-receptor pairs. Using a glycan array screen, we identified the novel capacity of the TIM-3 Ig domain to recognize specific carbohydrate moieties, suggesting a role for carbohydrate modification along with protein epitopes in TIM ligand recognition. Identification of the carbohydrate-binding capacity of TIM proteins helps explain the diversity of ligands recognized by this family and adds to our understanding of homotypic and heterotypic interactions between TIM family members.
T细胞免疫球蛋白结构域和粘蛋白结构域（TIM）蛋白构成了一个保守的跨膜细胞表面糖蛋白家族，由多种组织表达。每个TIM蛋白都包含一个单一的V型免疫球蛋白结构域、一个糖基化的粘蛋白样结构域、一个跨膜结构域和一个胞质结构域。TIM蛋白可识别多种配体，包括H-铁蛋白、半乳糖凝集素-9以及其他TIM家族成员。在本研究中，我们证明小鼠TIM-1、-3和-4的免疫球蛋白结构域与小鼠脾细胞和几种非小鼠细胞系表达的配体呈钙依赖性结合，表明存在非物种特异性的配体识别。此外，各种TIM家族免疫球蛋白结构域与表面表达的TIM-1和TIM-4的家族内相互作用需要完整的TIM-1和TIM-4糖基化粘蛋白茎。重要的是，我们还发现了TIM在形成配体-受体对中存在以前未被认识的同型相互作用的潜力。通过聚糖阵列筛选，我们确定了TIM-3免疫球蛋白结构域识别特定碳水化合物部分的新能力，这表明碳水化合物修饰以及蛋白质表位在TIM配体识别中发挥作用。TIM蛋白碳水化合物结合能力的鉴定有助于解释该家族识别的配体多样性，并增进我们对TIM家族成员之间同型和异型相互作用的理解。
