Cell-surface-anchored immunoglobulin superfamily (IgSF) proteins are widespread throughout the human proteome, forming crucial components of diverse biological processes including immunity, cell-cell adhesion, and carcinogenesis. IgSF proteins generally function through protein-protein interactions carried out between extracellular, membrane-bound proteins on adjacent cells, known as trans-binding interfaces. These protein-protein interactions constitute a class of pharmaceutical targets important in the treatment of autoimmune diseases, chronic infections, and cancer. A molecular-level understanding of IgSF protein-protein interactions would greatly benefit further drug development. A critical step toward this goal is the reliable identification of IgSF trans-binding interfaces. We propose a novel combination of structure and sequence information to identify trans-binding interfaces in IgSF proteins. We developed a structure-based binding interface prediction approach that can identify broad regions of the protein surface that encompass the binding interfaces and suggests that IgSF proteins possess binding supersites. These interfaces could theoretically be pinpointed using sequence-based conservation analysis, with performance approaching the theoretical upper limit of binding interface prediction accuracy, but achieving this in practice is limited by the current ability to identify an appropriate multiple sequence alignment for conservation analysis. However, an important contribution of combining the two orthogonal methods is that agreement between these approaches can estimate the reliability of the predictions. This approach was benchmarked on the set of 22 IgSF proteins with experimentally solved structures in complex with their ligands. Additionally, we provide structure-based predictions and reliability scores for the 62 IgSF proteins with known structure but yet uncharacterized binding interfaces.

中文翻译：

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在免疫球蛋白超家族中发现受体-配体界面。

细胞表面锚定的免疫球蛋白超家族（IgSF）蛋白广泛分布于整个人类蛋白质组中，形成了包括免疫，细胞与细胞粘附和致癌作用在内的多种生物学过程的关键组成部分。IgSF蛋白通常通过在相邻细胞上的细胞外，膜结合蛋白之间进行的蛋白-蛋白相互作用而起作用，这被称为反式结合界面。这些蛋白质-蛋白质相互作用构成一类药物靶标，在治疗自身免疫性疾病，慢性感染和癌症中很重要。从分子水平上了解IgSF蛋白质-蛋白质相互作用将大大有利于进一步的药物开发。朝此目标迈出的关键一步是对IgSF反式结合界面的可靠识别。我们提出了一种结构和序列信息的新型组合，以识别IgSF蛋白中的反式结合界面。我们开发了一种基于结构的结合界面预测方法，该方法可以确定包含结合界面的蛋白质表面的广泛区域，并表明IgSF蛋白具有结合超位点。这些接口理论上可以使用基于序列的保守性分析来精确定位，其性能接近结合界面预测精度的理论上限，但是在实践中实现这一目标受到当前为保护性分析识别合适的多序列比对的能力的限制。但是，将两种正交方法组合在一起的重要贡献在于，这些方法之间的一致性可以估计预测的可靠性。该方法以22种IgSF蛋白质为基准，这些蛋白质具有经实验解析的结构及其配体。此外，我们提供了具有已知结构但尚未表征的结合界面的62种IgSF蛋白的基于结构的预测和可靠性评分。