7a8u
Crystal structure of sarcomeric protein FATZ-1 (d91-FATZ-1 construct) in complex with rod domain of alpha-actinin-2
Structural highlights
DiseaseACTN2_HUMAN Defects in ACTN2 are the cause of cardiomyopathy dilated type 1AA (CMD1AA) [MIM:612158. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.[1] FunctionACTN2_HUMAN F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein. Publication Abstract from PubMedIn sarcomeres, alpha-actinin cross-links actin filaments and anchors them to the Z-disk. FATZ (filamin-, alpha-actinin-, and telethonin-binding protein of the Z-disk) proteins interact with alpha-actinin and other core Z-disk proteins, contributing to myofibril assembly and maintenance. Here, we report the first structure and its cellular validation of alpha-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 alpha-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 alpha-actinin-2 preferential orientation in Z-disk. Last, we uncover FATZ-1 ability to phase-separate and form biomolecular condensates with alpha-actinin-2, raising the question whether FATZ proteins can create an interaction hub for Z-disk proteins through membraneless compartmentalization during myofibrillogenesis. Order from disorder in the sarcomere: FATZ forms a fuzzy but tight complex and phase-separated condensates with alpha-actinin.,Sponga A, Arolas JL, Schwarz TC, Jeffries CM, Rodriguez Chamorro A, Kostan J, Ghisleni A, Drepper F, Polyansky A, De Almeida Ribeiro E, Pedron M, Zawadzka-Kazimierczuk A, Mlynek G, Peterbauer T, Doto P, Schreiner C, Hollerl E, Mateos B, Geist L, Faulkner G, Kozminski W, Svergun DI, Warscheid B, Zagrovic B, Gautel M, Konrat R, Djinovic-Carugo K Sci Adv. 2021 May 28;7(22):eabg7653. doi: 10.1126/sciadv.abg7653. Print 2021 May. PMID:34049882[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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