Functional divergence of the sarcomeric myosin, MYH7b, supports species-specific biological roles.
Lindsey A. Lee, Samantha K. Barrick, Artur Meller, Jonathan Walklate, Jeffrey M. Lotthammer, Jian Wei Tay, W. Tom Stump, Gregory Bowman, Michael A. Geeves, Michael J. Greenberg, and Leslie A. Leinwand
Journal of Biological Chemistry , (2022)Abstract
Myosin heavy chain 7b (MYH7b) is an evolutionarily ancient member of the sarcomeric myosin family, which typically supports striated muscle function. However, in mammals alternative splicing prevents MYH7b protein production in cardiac and most skeletal muscles and limits expression to a subset of specialized muscles and certain non-muscle environments. In contrast, MYH7b protein is abundant in python cardiac and skeletal muscles. Although the MYH7b expression pattern diverges in mammals versus reptiles, MYH7b shares high sequence identity across species. So, it remains unclear how mammalian MYH7b function may differ from that of other sarcomeric myosins and whether human and python MYH7b motor functions diverge as their expression patterns suggest. Thus, we generated recombinant human and python MYH7b protein and measured their motor properties to investigate any species-specific differences in activity. Our results reveal that despite having similar working strokes, the MYH7b isoforms have slower actin-activated ATPase cycles and actin sliding velocities than human cardiac β-MyHC. Furthermore, python MYH7b is tuned to have slower motor activity than human MYH7b due to slower kinetics of the mechanochemical cycle. We found that the MYH7b isoforms adopt a higher proportion of myosin heads in the ultra-slow, super-relaxed state compared to human cardiac β-MyHC. These findings are supported by molecular dynamics simulations that predict MYH7b preferentially occupies myosin active site conformations similar to those observed in the structurally inactive state. Together, these results suggest that MYH7b is specialized for slow, energy-conserving motor activity and that differential tuning of MYH7b orthologs contributes to species-specific biological roles.