The Structure and Regulation of Human Muscle α-Actinin

Summary

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.

Graphical Abstract

Highlights

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  Structure of human α-actinin-2 in an autoinhibited closed conformation

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  Facilitation of PIP2-induced allosteric modulation for opening and titin binding

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  Essentiality of structural flexibility for crosslinking antiparallel F-actin

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  Relevance for the intramolecular pseudoligand regulation mechanism of the spectrin family

Abstract

The structure of human α-actinin, the major component of the basic contractile units of muscles, reveals a unique phosphoinositide-based mechanism of its regulation, as well as assembly.