Control of actin dynamics through the regulation of tropomodulin

Scripps Research Institute, The, La Jolla CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Tropomodulins (Tmods) interact with both tropomyosin (TM) and actin to prevent depolymerization and elongation of actin filament pointed ends, thereby regulating the length of striated muscle thin filaments. The importance of Tmod regulation of actin dynamics is underscored by the finding that changes in Tmod levels in the mouse heart lead to sarcomeric disarray, a phenotype found in human myopathies. Isoforms of Tmod and TM are spatially and temporally regulated and exhibit different binding affinities, suggesting that variations in sarcomeric thin filament lengths in different striated muscles could be determined by specific interactions between Tmod and TM isoforms. As sarcomeric thin filament length controls maximum force generation and contraction efficiency in myofibrils, regulation of the Tmod:TM interaction is likely to be critical for striated muscle function. I hypothesize that sarcomeric thin filament length in striated muscle is regulated by the affinity of the Tmod:TM interaction, such that a higher interaction affinity will result in shorter thin filaments and a lower affinity will produce longer filaments. Additionally, I predict that the affinities between Tmod and TM are isoform specific and that expression of each isoform is tightly regulated throughout muscle development. In this way, different combinations of Tmod and TM isoforms will result in different thin filament lengths in distinct muscle types. To investigate the mechanism for sarcomeric thin filament regulation in striated muscle, I will use a combination of molecular, biochemical, and cellular biological techniques to directly address: 1) the correlation between thin filament length and Tmod and TM isoform expression in striated muscle, 2) the interaction affinities between Tmod and TM isoforms expressed in striated muscle, and 3) how altered Tmod:TM interactions affect sarcomeric thin filament length. These studies will elucidate the molecular basis of sarcomeric thin filament length regulation and provide valuable insight into the roles of actin filament dynamics in the manifestation of myopathies. Relevance to public health: Muscle contraction is generated by movements within repeated contractile units of the muscle cytoskeleton called sarcomeres. Sarcomeres are highly organized and regulated such that disruption of sarcomeric organization leads to myopathies, degenerative diseases that effect the contraction of skeletal and cardiac muscle. Therefore, investigating the mechanism of sarcomere assembly and organization will provide further understanding of the causes of human myopathies and lead to better treatments and cures. [unreadable] [unreadable] [unreadable]