Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes

Abstract

Cardiac β-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human β-cardiac myosin IHM quasi-atomic model, we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls. HCM variants, 72% that changed electrostatic charges, disproportionately altered IHM interaction residues (expected 23%; HCM 54%, p=2.6×10−19; DCM 26%, p=0.66; controls 20%, p=0.23). HCM variant locations predict impaired IHM formation and stability, and attenuation of the SRX state - accounting for altered contractility, reduced diastolic relaxation, and increased energy consumption, that fully characterizes HCM pathogenesis.DOI: http://dx.doi.org/10.7554/eLife.24634.001

Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function

“…In relaxed rabbit psoas muscle, 70% of all heads are parallel to the fiber axis, whilẽ 30% of all heads are perpendicular , implying that the head population comprises 50% blocked heads (all parallel), 20% docked free heads (parallel) and 30% swaying free heads (perpendicular). It has been suggested that D s depends on muscle type and that D s = 2/(1 + R) where R = N par /N per is the ratio of the number of heads detected in parallel (N par ) and perpendicular (N per ) conformations (Alamo et al 2017b). Therefore, in skeletal muscle, R = 0.70/ 0.3 = 2.3 so D s = 0.60, i.e.…”

“…c Further calculations of PDB 3DTP and PDB 3JBH show that the scattering of the two models is nearly identical at wide angles. SAXS and error calculation described in Alamo et al (2017b) Twelve tubes are seen in Limulus, Tityus and Schistosoma fourstranded filament 3D reconstructions, while 21 or 9 subfilaments are expected in the seven-stranded or three-stranded scallop and cardiac muscle as proposed by Wray's subfilament model ( Fig. 3f) (Wray 1979).…”

“…These two different heads populations have functional consequences on the sarcomere relaxation and contraction (Fig. 11) as well as important implications on the effect of mutations associated with HCM due to the involvement of these extra recruited blocked heads on the hypercontractility caused by HCM (Alamo et al 2017b).…”

“…SRX/DRX energetics ratio: It has been suggested that the estimated ratio of heads in the SRX and the disordered relaxed (DRX, Fig. 7b) states is ε = SRX/DRX = (2-D s )/ D s and that it depends on muscle type (Alamo et al 2017b). Therefore, as D s = 0.6 in skeletal muscle is ε = 2.3, it is possible to predict an estimated 2.3-fold reduction of ATP hydrolysis.…”

Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

“…For instance, if LVNC exists on a clinical spectrum with mutational burden playing a key role, we must determine how to identify and interpret contributory rare variants and distinguish these from benign bystanders. Recent work by Homburger et al 28 and Alamo et al 29 demonstrate promising use cases to address this, by combining knowledge of the protein structure of several sarcomeric proteins, with computational comparisons of population and cardiomyopathy cohorts, to identify regions enriched for disease-causing variants. These identified critical regions can assist in adjudicating the significance of genetic variants, particularly the often-elusive novel missense variants.…”