Crystal structure and functional interpretation of the erythrocyte spectrin tetramerization domain complex
Crystal structure and functional interpretation of the erythrocyte spectrin tetramerization domain complex
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DOI：
10.1182/blood-2010-01-261396
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发表时间：
2010-06-10
期刊：
影响因子：
20.3
通讯作者：
Speicher, David W.
中科院分区：
文献类型：
--
作者：
Ipsaro, Jonathan J.;Harper, Sandra L.;Speicher, David W.
血影蛋白作为膜骨架的主要成分，赋予红细胞膜完整性和柔韧性。虽然这个网络涉及许多相互作用，最常见的溶血性贫血突变，破坏红细胞形态影响血影蛋白四聚化结构域。尽管临床上对由此产生的疾病（遗传性椭圆形红细胞增多症和焦斑红细胞增多症）了解很多，但血影蛋白四聚体及其被遗传性贫血突变破坏的详细结构基础仍然难以捉摸。因此，为了提供对血影蛋白组装和四聚体位点突变的进一步了解，已经确定了血影蛋白四聚化结构域复合物的晶体结构。在结构上，这个复杂的多重复血影蛋白片段显示出惊人的相似之处，相互作用的四聚体位点区域形成一个中央，复合重复。该结构鉴定了与β-血影蛋白结合后发生的α-血影蛋白的构象变化，并报告了β-血影蛋白四聚化结构域的第一个结构。相互作用表面的分析表明，一个广泛的界面为主的疏水接触和静电互补性的补充。进化保守残基的分析表明，可能形成重要的相互作用的额外的表面。最后，遗传性贫血相关的突变映射到结构上表明，大多数，但不是全部，局部遗传性贫血突变映射到相互作用的结构域。这些突变的潜在分子效应进行了描述。（血。2010;115（23）：4843-4852）
As the principal component of the membrane skeleton, spectrin confers integrity and flexibility to red cell membranes. Although this network involves many interactions, the most common hemolytic anemia mutations that disrupt erythrocyte morphology affect the spectrin tetramerization domains. Although much is known clinically about the resulting conditions (hereditary elliptocytosis and pyropoikilo-cytosis), the detailed structural basis for spectrin tetramerization and its disruption by hereditary anemia mutations remains elusive. Thus, to provide further insights into spectrin assembly and tetramer site mutations, a crystal structure of the spectrin tetramerization domain complex has been determined. Architecturally, this complex shows striking resemblance to multirepeat spectrin fragments, with the interacting tetramer site region forming a central, composite repeat. This structure identifies conformational changes in alpha-spectrin that occur upon binding to beta-spectrin, and it reports the first structure of the beta-spectrin tetramerization domain. Analysis of the interaction surfaces indicates an extensive interface dominated by hydrophobic contacts and supplemented by electrostatic complementarity. Analysis of evolutionarily conserved residues suggests additional surfaces that may form important interactions. Finally, mapping of hereditary anemia-related mutations onto the structure demonstrate that most, but not all, local hereditary anemia mutations map to the interacting domains. The potential molecular effects of these mutations are described. (Blood. 2010;115(23):4843-4852)