Ribeiro Euripedes de Almeida, Pinotsis Nikos, Ghisleni Andrea, Salmazo Anita, Konarev Petr V, Kostan Julius, Sjöblom Björn, Schreiner Claudia, Polyansky Anton A, Gkougkoulia Eirini A, Holt Mark R, Aachmann Finn L, Zagrović Bojan, Bordignon Enrica, Pirker Katharina F, Svergun Dmitri I, Gautel Mathias, Djinović-Carugo Kristina
Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
British Heart Foundation Centre of Research Excellence, Randall Division for Cell and Molecular Biophysics and Cardiovascular Division, King's College London, London SE1 1UL, UK.
Cell. 2014 Dec 4;159(6):1447-60. doi: 10.1016/j.cell.2014.10.056. Epub 2014 Nov 26.
The spectrin superfamily of proteins plays key roles in assembling the actin cytoskeleton in various cell types, crosslinks actin filaments, and acts as scaffolds for the assembly of large protein complexes involved in structural integrity and mechanosensation, as well as cell signaling. α-actinins in particular are the major actin crosslinkers in muscle Z-disks, focal adhesions, and actin stress fibers. We report a complete high-resolution structure of the 200 kDa α-actinin-2 dimer from striated muscle and explore its functional implications on the biochemical and cellular level. The structure provides insight into the phosphoinositide-based mechanism controlling its interaction with sarcomeric proteins such as titin, lays a foundation for studying the impact of pathogenic mutations at molecular resolution, and is likely to be broadly relevant for the regulation of spectrin-like proteins.
血影蛋白超家族蛋白在多种细胞类型中组装肌动蛋白细胞骨架、交联肌动蛋白丝，并作为参与结构完整性、机械传感以及细胞信号传导的大型蛋白质复合物组装的支架发挥关键作用。特别是α-辅肌动蛋白是肌肉Z盘、粘着斑和肌动蛋白应力纤维中的主要肌动蛋白交联剂。我们报告了来自横纹肌的200 kDaα-辅肌动蛋白-2二聚体的完整高分辨率结构，并在生化和细胞水平上探讨了其功能意义。该结构为基于磷酸肌醇的机制提供了见解，该机制控制其与肌节蛋白（如肌联蛋白）的相互作用，为在分子分辨率下研究致病突变的影响奠定了基础，并且可能与血影蛋白样蛋白的调节广泛相关。
