Department of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biosciences, University of California, San Francisco, California.
Protein Sci. 2010 Mar;19(3):412-28. doi: 10.1002/pro.320.
Solute carriers are eukaryotic membrane proteins that control the uptake and efflux of solutes, including essential cellular compounds, environmental toxins, and therapeutic drugs. Solute carriers can share similar structural features despite weak sequence similarities. Identification of sequence relationships among solute carriers is needed to enhance our ability to model individual carriers and to elucidate the molecular mechanisms of their substrate specificity and transport. Here, we describe a comprehensive comparison of solute carriers. We link the proteins using sensitive profile-profile alignments and two classification approaches, including similarity networks. The clusters are analyzed in view of substrate type, transport mode, organism conservation, and tissue specificity. Solute carrier families with similar substrates generally cluster together, despite exhibiting relatively weak sequence similarities. In contrast, some families cluster together with no apparent reason, revealing unexplored relationships. We demonstrate computationally and experimentally the functional overlap between representative members of these families. Finally, we identify four putative solute carriers in the human genome. The solute carriers include a biomedically important group of membrane proteins that is diverse in sequence and structure. The proposed classification of solute carriers, combined with experiment, reveals new relationships among the individual families and identifies new solute carriers. The classification scheme will inform future attempts directed at modeling the structures of the solute carriers, a prerequisite for describing the substrate specificities of the individual families.
溶质载体是真核细胞膜蛋白，控制溶质（包括必需的细胞化合物、环境毒素和治疗药物）的摄取和外排。尽管溶质载体的序列相似性较弱，但它们具有相似的结构特征。识别溶质载体之间的序列关系，有助于提高我们对个体载体进行建模的能力，并阐明其底物特异性和转运的分子机制。在这里，我们描述了对溶质载体的全面比较。我们使用敏感的轮廓-轮廓比对和两种分类方法（包括相似性网络）将这些蛋白质联系起来。根据底物类型、运输方式、生物保守性和组织特异性来分析这些簇。尽管具有相对较弱的序列相似性，但具有相似底物的溶质载体家族通常聚集在一起。相比之下，一些家族聚集在一起没有明显的原因，揭示了尚未探索的关系。我们通过计算和实验证明了这些家族的代表性成员之间存在功能重叠。最后，我们确定了人类基因组中的四个推定的溶质载体。溶质载体包括一组在序列和结构上多样化的具有重要生物医学意义的膜蛋白。所提出的溶质载体分类方法结合实验揭示了各个家族之间的新关系，并确定了新的溶质载体。该分类方案将为未来尝试描述溶质载体的结构提供信息，这是描述各个家族的底物特异性的前提。
