Key result
High-resolution cryo-EM structures of skeletal a-actin, cardiac a-actin, b-actin, and g-actin revealed isoform-specific conformations of the N-terminus that establish distinct binding interfaces.
Why the study?
Identifying how the structure of actin isoforms relates to function is important for understanding normal cytoskeletal physiology, despite high sequence conservation.
May inform cardiac actin targeting; leaves open isoform-PTM effects in human disease.
Actin isoforms organize into distinct networks that are essential for the normal function of eukaryotic cells. Despite a high level of sequence and structure conservation, subtle changes in their design principles determine the interaction with myosin motors and actin-binding proteins. The functional diversity is further increased by posttranslational modifications (PTMs). Therefore, identifying how the structure of actin isoforms relates to function is important for our understanding of normal cytoskeletal physiology. Here, we report the high-resolution structures of filamentous skeletal α-actin (3.37Å), cardiac α-actin (3.07Å), ß-actin (2.99Å), and γ-actin (3.38Å) in the Mg 2+ ·ADP state with their native PTMs. The structures revealed isoform-specific conformations of the N-terminus that shifts closer to the filament surface upon myosin binding, thereby establishing isoform-specific interfaces. Retropropagated structural changes further show that myosin binding modulates actin filament structure. Further, our structures enabled us to reveal the location of disease-causing mutations and to analyze them with respect to known locations of PTMs. Collectively, the previously unknown structures of single-isotype, posttranslationally modified bare cardiac α-actin, ß-actin, and γ-actin reveal general principles, similarities, and differences between isoforms. They complement the repertoire of known actin structures and allow for a comprehensive understanding of in vitro and in vivo functions of actin isoforms.
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Arora et al. (2022) studied this question. Cryo-electron microscopy of actin isoforms was evaluated on High-resolution structures of filamentous actin isoforms. High-resolution cryo-EM structures of skeletal a-actin, cardiac a-actin, b-actin, and g-actin revealed isoform-specific conformations of the N-terminus that establish distinct binding interfaces.
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