University of Vienna: Building muscles from liquids – phase separation in the Z-disc

The lab of Kristina Djinovic-Carugo and their collaborators report the first structure of FATZ-1 in complex with a-actinin, two important proteins found in the Z-disc of muscle fibers. The Z-disc is a supramolecular structure that anchors actin filaments in skeletal muscle. Intriguingly, FATZ-1, which is an intrinsically disordered protein implicated in the biogenesis of the Z-disc, also shows a propensity to form biomolecular condensates. The work raises interesting questions about the role of liquid-liquid phase separation in the formation of these structures. The study is published in Science Advances.

Every time our hearts beat, or we move, the ATP-fueled interaction of myosin motor proteins and actin filaments make our muscles contract. Actin filaments require a stable anchoring structure, a role fulfilled by Z-discs. These structures form the boundary of adjacent sarcomeres, the basic contractile units of muscles. In the Z-disc, a-actinin crosslinks the actin filaments of muscle fibers to provide structural rigidity. FATZ-1 serves as a protein-protein interaction hub, linking a set of Z-disc components. The team of Kristina Djinovic-Carugo and their collaborators have now obtained the first structural insights into the molecular interactions of the two proteins. “Using a combination of approaches, we have modeled an integrative structure of a-actinin with FATZ-1”, explains group leader Kristina Djinovic-Carugo. “We found that they form a structurally ambivalent “fuzzy” complex, in which the proteins tightly associate at two sites but FATZ-1 remains mostly disordered”.

Z-discs nucleate from so called Z-bodies, assemblies of proteins that include a-actinin and FATZ-1. Z-bodies are described as aggregates or puncta that grow in size, fuse together and associate with other proteins to form mature Z-discs. The process is reminiscent of membrane-less organelles that form through liquid-liquid phase separation and create functionally distinct units in cells. “The Z-disc is arranged in a highly ordered paracrystalline, tetragonal structure”, explains group leader Kristina Djinovic-Carugo. “Therefore, there must be mechanisms that explain how Z-bodies give rise to these higher order, stable structures”. The scientists observed that FATZ-1 formed biomolecular condensates in vitro, which could be dissolved by adding increasing concentrations of a-actinin. Given the role of FATZ-1 as a protein interaction hub, the scientists propose that “the entire sarcomere biogenesis could start from liquid condensates”, as Kristina Djinovic explains. In their model, FATZ proteins are scaffolds that concentrate the basic building blocks of myofibrils.

Supported by a recent FWF doc.funds the lab now aims to test this hypothesis with pluripotent stem cell derived heart muscle cells. “The aim of this project is to delineate the phase diagram of FATZ-based biomolecular condensates in order to understand what the concentrations of scaffold and client proteins needed for their formation are, and what the hierarchy and interdependence of the interaction partners is”. The findings could have implications for the biogenesis of other macromolecular assemblies: “Our work aims to uncover general principles that govern how ordered systems arise from initial disorder”, concludes Kristina Djinovic-Carugo.

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