Sponga Antonio, Arolas Joan L, Schwarz Thomas C, Jeffries Cy M, Rodriguez Chamorro Ariadna, Kostan Julius, Ghisleni Andrea, Drepper Friedel, Polyansky Anton, De Almeida Ribeiro Euripedes, Pedron Miriam, Zawadzka-Kazimierczuk Anna, Mlynek Georg, Peterbauer Thomas, Doto Pierantonio, Schreiner Claudia, Hollerl Eneda, Mateos Borja, Geist Leonhard, Faulkner Georgine, Kozminski Wiktor, Svergun Dmitri I, Warscheid Bettina, Zagrovic Bojan, Gautel Mathias, Konrat Robert, Djinović-Carugo Kristina
Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Campus Vienna Biocenter 5, A-1030 Vienna, Austria.
European Molecular Biology Laboratory (EMBL), Hamburg Unit, Hamburg, Germany.
Sci Adv. 2021 May 28;7(22). doi: 10.1126/sciadv.abg7653. Print 2021 May.
In sarcomeres, α-actinin cross-links actin filaments and anchors them to the Z-disk. FATZ (filamin-, α-actinin-, and telethonin-binding protein of the Z-disk) proteins interact with α-actinin and other core Z-disk proteins, contributing to myofibril assembly and maintenance. Here, we report the first structure and its cellular validation of α-actinin-2 in complex with a Z-disk partner, FATZ-1, which is best described as a conformational ensemble. We show that FATZ-1 forms a tight fuzzy complex with α-actinin-2 and propose an interaction mechanism via main molecular recognition elements and secondary binding sites. The obtained integrative model reveals a polar architecture of the complex which, in combination with FATZ-1 multivalent scaffold function, might organize interaction partners and stabilize α-actinin-2 preferential orientation in Z-disk. Last, we uncover FATZ-1 ability to phase-separate and form biomolecular condensates with α-actinin-2, raising the question whether FATZ proteins can create an interaction hub for Z-disk proteins through membraneless compartmentalization during myofibrillogenesis.
在肌节中，α-辅肌动蛋白交联肌动蛋白丝并将它们锚定到Z盘。FATZ（Z盘的细丝蛋白、α-辅肌动蛋白和隐钙蛋白结合蛋白）与α-辅肌动蛋白及其他Z盘核心蛋白相互作用，有助于肌原纤维的组装和维持。在此，我们报道了α-辅肌动蛋白-2与Z盘伴侣FATZ-1形成复合物的首个结构及其细胞验证，该复合物最好描述为一种构象集合体。我们表明，FATZ-1与α-辅肌动蛋白-2形成紧密的模糊复合物，并通过主要分子识别元件和二级结合位点提出了一种相互作用机制。所获得的整合模型揭示了该复合物的极性结构，结合FATZ-1的多价支架功能，可能会组织相互作用伙伴并稳定α-辅肌动蛋白-2在Z盘中的优先取向。最后，我们发现FATZ-1具有与α-辅肌动蛋白-2相分离并形成生物分子凝聚物的能力，这就提出了一个问题，即FATZ蛋白在肌原纤维生成过程中是否能够通过无膜区室化作用为Z盘蛋白创建一个相互作用枢纽。
