Fig. 4
A Tropomyosins form α-helical coiled-coil dimers via a seven residue repeat motif in their amino acid sequence [a-b-c-d-e-f-g] [3]. This structure is stabilised by the hydrophobic interactions between a-a’ and d-d’ (shaded squares) together with the hydrophilic interactions between g-e’ and e-g’ (shaded circles) of the two tropomyosin chains. Actin binds to tropomyosin electrostatically at two points, at actin position Asp25 and a cluster of amino acids that includes actin at position Lys326. B The 3-dimensional structure of one of the two tropomyosin molecules (dark grey) interfacing with the actin double helix (light grey) at actin at position Asp25 (black) is shown here. C The α-tropomyosinslow amino acid sequence (annotated using the 1-letter amino acid abbreviation) is depicted here. The position of the amino acid in relation to the seven residue repeat motif of tropomyosin is indicated directly below the amino acid sequence. The structure of tropomyosin is further divided into seven quasi-repeating periods (periods 1-7) and α-bands and ß-bands. The purple circles highlight residues interacting with actin at position Asp25. Known pathogenic variants of the TPM3 gene that interact with actin at position Asp25 that result in an alteration of calcium ion sensitivity are shown here. Pathogenic variants that increase calcium ion sensitivity are written are underlined, while those that decrease Ca2+ sensitivity are italicised (annotations using their 1 letter amino acid abbreviation in brackets). The variant observed in our patient, p.Ser246Leu (S246L) is written in bold.