Key result
Cryo-EM shows non-muscle tropomyosin isoforms Tpm1.6 and Tpm3.2 follow distinct actin paths without altering conformation.
Why the study?
The molecular mechanisms by which non-redundant non-muscle tropomyosin isoforms differentially control interactions of other proteins with actin filaments have remained elusive.
Cryo-EM structures reveal that non-muscle tropomyosin isoforms Tpm1.6 and Tpm3.2 follow distinct paths along the actin filament, providing a structural basis for their specific biochemical activities.
No immediate clinical implications; leaves open isoform-specific actin regulation in cardiovascular cells.
The actin cytoskeleton is critical for cell migration, morphogenesis, endocytosis, organelle dynamics, and cytokinesis. To support diverse cellular processes, actin filaments form a variety of structures with specific architectures and dynamic properties. Key proteins specifying actin filaments are tropomyosins. Non-muscle cells express several functionally non-redundant tropomyosin isoforms, which differentially control the interactions of other proteins, including myosins and ADF/cofilin, with actin filaments. However, the underlying molecular mechanisms have remained elusive. By determining the cryogenic electron microscopy structures of actin filaments decorated by two functionally distinct non-muscle tropomyosin isoforms, Tpm1.6 and Tpm3.2, we reveal that actin filament conformation remains unaffected upon binding. However, Tpm1.6 and Tpm3.2 follow different paths along the actin filament major groove, providing an explanation for their incapability to co-polymerize on actin filaments. We also elucidate the molecular basis underlying specific roles of Tpm1.6 and Tpm3.2 in myosin II activation and protecting actin filaments from ADF/cofilin-catalyzed severing.
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Selvaraj et al. (2022) studied Actin cytoskeleton dynamics. Cryogenic electron microscopy was evaluated on Molecular mechanisms of Tpm1.6 and Tpm3.2 binding to actin filaments. Cryogenic electron microscopy structures reveal that non-muscle tropomyosin isoforms Tpm1.6 and Tpm3.2 follow different paths along the actin filament major groove without altering its conformation.
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