Order from disorder in the sarcomere: FATZ forms a fuzzy but tight complex and phase-separated condensates with α-actinin
Antonio Sponga, Joan L. Arolas, Thomas C. Schwarz, Cy M. Jeffries, Ariadna Rodriguez Chamorro, Július Košťan, Andrea Ghisleni, Friedel Drepper, Anton A. Polyansky, Euripedes de Almeida Ribeiro, Miriam Pedron, Anna Zawadzka‐Kazimierczuk, Georg Mlynek, Thomas Peterbauer, Pierantonio Doto, Claudia Schreiner, Eneda Höllerl, Borja Mateos, Leonhard Geist, Georgine Faulkner, Wiktor Koźmiński, Dmitri I. Svergun, Bettina Warscheid, Bojan Žagrović, Mathias Gautel, Robert Konrat, Kristina Djinović‐Carugo
Abstract
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.