HCM-causing mutations in the troponin T-binding region of tropomyosin increased Ca2+ sensitivity and impaired relaxation, whereas the I172T mutation decreased Ca2+ sensitivity.
Various HCM-causing mutations in cardiac tropomyosin affect its structural and functional properties differently, suggesting diverse molecular mechanisms for HCM pathogenesis.
Hypertrophic cardiomyopathy (HCM) is a severe heart disease caused by missense mutations in genes encoding sarcomeric proteins of cardiac muscle. Many of these mutations are identified in the gene encoding the cardiac isoform of tropomyosin (Tpm), an α-helical coiled-coil actin-binding protein that plays a key role in Ca 2+ -regulated contraction of cardiac muscle. We employed various methods to characterize structural and functional features of recombinant human Tpm species carrying HCM mutations that lie either within the troponin T-binding region in the C-terminal part of Tpm (E180G, E180V, and L185R) or near this region (I172T). The results of our structural studies show that all these mutations affect, although differently, the thermal stability of the C-terminal part of the Tpm molecule: mutations E180G and I172T destabilize this part of the molecule, whereas mutation E180V strongly stabilizes it. Moreover, various HCM-causing mutations have different and even opposite effects on the stability of the Tpm–actin complexes. Studies of reconstituted thin filaments in the in vitro motility assay have shown that those HCM-associated mutations that lie within the troponin T-binding region of Tpm similarly increase the Ca 2+ sensitivity of the sliding velocity of the filaments and impair their relaxation properties, causing a marked increase in the sliding velocity in the absence of Ca 2+, while mutation I172T decreases the Ca 2+ sensitivity and has no influence on the sliding velocity under relaxing conditions. Finally, our data demonstrate that various HCM mutations can differently affect the structural and functional properties of Tpm and cause HCM by different molecular mechanisms.
Matyushenko et al. (Thu,) conducted a other in Hypertrophic cardiomyopathy. HCM-causing mutations in cardiac tropomyosin (E180G, E180V, L185R, I172T) was evaluated on Structural and functional properties of Tpm (thermal stability, Tpm-actin complex stability, Ca2+ sensitivity of sliding velocity). HCM-causing mutations in the troponin T-binding region of tropomyosin increased Ca2+ sensitivity and impaired relaxation, whereas the I172T mutation decreased Ca2+ sensitivity.