Skeletal muscle myopathy mutations at the actin tropomyosin interface that cause gain- or loss-of-function

It is well known that the regulation of muscle contraction relies on the ability of tropomyosin to switch between different positions on the actin filament, but it is still not well understood which amino acids are directly involved in the different states of the interaction. Recently the structure of the actin-tropomyosin interface has been determined both in the absence and presence of myosin heads. Interestingly, a number of mutations in tropomyosin that are associated with skeletal muscle myopathy are located within this interface. We first give an overview of the functional effect of mutations on amino acids that are involved in the contact with actin asp25, which represent a pattern repeated seven times along tropomyosin. It is explained how some of these amino acids (R167 and R244) which are thought to be involved in a salt bridge contact with actin in the closed state can produce a loss-of-function when mutated, while other positively charged tropomyosin amino acids positioned on the downstream side of the contact (K7, K49, R91, K168) can produce a gain-of-function when mutated. We then consider mutations of amino acids involved in another salt bridge contact between the two proteins in the closed state, actin K326N (which binds on five different points of tropomyosin) and tropomyosin Delta E139 and E181K, and we report how all of these mutations produce a gain-of-function. These observations can be important to validate the proposed structures and to understand more deeply how mutations affect the function of these proteins and to enable prediction of their outcomes.