Periodicities designed in the tropomyosin sequence and structure define its functions

Abstract

Tropomyosin is an actin binding protein that regulates actin filament dynamics and its interactions with actin binding proteins such as myosin, tropomodulin, formin, Arp2/3 and ADF-cofilin in most eukaryotic cells. Tropomyosin is the prototypical two-chained, α-helical coiled coil protein that associates end-to-end and binds to both sides of the actin filament. Each tropomyosin molecule spans four to seven actin monomers in the filament, depending on the size of the tropomyosin. Tropomyosins have a periodic heptad repeat sequence that is characteristic of coiled coil proteins as well as additional periodicities required for its interaction with the actin filament, where each periodic repeat interacts with one actin molecule. This review addresses the role of periodic features of the Tm molecule in carrying out its universal functions of binding to the actin filament and its regulation and the specific features that may determine the isoform specificity of tropomyosins.

Keywords: actin filament; coiled coil; cytoskeleton; muscle regulation; tropomyosin.

Figure 1. Helical wheel representation of a coiled coil showing the heptad repeats. Heptad repeats are labeled a-g and a’-g’ on the two helices, where a and d are hydropohobic residues, e and g are acidic or basic residues and b, c, and f are surface residues (from Mason et al.).

Figure 2. Tropomyosin gene structure in animals. Exon organization and alignment of the vertebrate and invertebrate TPM genes. Alternatively spliced exons are labeled a-d in vertebrates and A-E in invertebrates (from Barua et al.).

Figure 3. Tropomyosin mutations at evolutionarily-conserved surface residues. The rat striated αTm sequence showing conserved b, c, and f residues that were mutated to Ala. Each mutant had 1–4 mutations within the first-half (magenta) of periods 1–7 or the second-half (cyan) of periods 2–6. The pattern of basic and acidic residues in the first-half of periods at positions f, b, and f are indicated by the blue (position f, basic residues) and red (positions b and f, acidic residues) boxes.^,,

Figure 4. Summary of contributions of conserved residues of individual periodic repeats to tropomyosin function. Tropomyosin residues important for actin binding (first-half of periods, magenta) and actomyosin regulation (second-half of periods, cyan) shown in the 7 Å striated muscle αTm structure (1C1G).