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Review
. 2013 Apr;70(7):1221-39.
doi: 10.1007/s00018-012-1131-1. Epub 2012 Sep 6.

Heavy and light roles: myosin in the morphogenesis of the heart

Jennifer England  1 , Siobhan Loughna
Affiliations
Review

Heavy and light roles: myosin in the morphogenesis of the heart

Jennifer England et al. Cell Mol Life Sci. 2013 Apr.

Abstract

Myosin is an essential component of cardiac muscle, from the onset of cardiogenesis through to the adult heart. Although traditionally known for its role in energy transduction and force development, recent studies suggest that both myosin heavy-chain and myosin light-chain proteins are required for a correctly formed heart. Myosins are structural proteins that are not only expressed from early stages of heart development, but when mutated in humans they may give rise to congenital heart defects. This review will discuss the roles of myosin, specifically with regards to the developing heart. The expression of each myosin protein will be described, and the effects that altering expression has on the heart in embryogenesis in different animal models will be discussed. The human molecular genetics of the myosins will also be reviewed.

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Figures

Fig. 1
Fig. 1
Schematic representation of a sarcomere. The thick and thin filaments overlap in the region of the A-band, with the I-band formed from the thin filaments only. The central M-line anchors the thick filaments and the Z-disk the thin filaments. Titin is found along the length of the sarcomere. Tropomyosin and the troponin complex interact with actin to form part of the thin filament
Fig. 2
Fig. 2
The assembly of myofibrils. a Formation of premyofibrils. Proteins assemble into structures known as premyofibrils, which characteristically contain α-actinin along the periphery of the cell, and nonmuscle myosin (NMHC) scattered between the actin. b Formation of nascent myofibrils. Muscle-specific myosin II isoforms and stabilizing proteins become incorporated into the myofibrils, with the myosin heavy-chain (MHC) proteins replacing NMHC. Titin is also expressed in the myofibril at this stage. c Formation of mature myofibrils. Nascent myofibrils fuse to form mature myofibrils, forming a highly organized sarcomeric structure
Fig. 3
Fig. 3
Simplified view of the relationship between the globular head of myosin heavy chain and the thin filament. The positions of tropomyosin and TnC, TnI, and TnT along the actin filament are illustrated. A magnification of the globular head shows the position of the actin-binding site, the ATP pocket, and the essential light chain (ELC) and regulatory light chain (RLC) binding domains. MHC myosin heavy chain, MLC myosin light chain, S1 subfragment-1, Tn troponin
Fig. 4
Fig. 4
Schematic diagram of the cross-bridge cycle. a ATP binds to the ATP-binding domain on the myosin head. b ATP is hydrolyzed to ADP and a phosphate allowing the myosin head to move towards the actin filament. c Binding of Ca2+ to troponin C (TnC) results in a conformational change in the troponin complex, allowing the movement of tropomyosin around the actin filament (as indicated by the purple arrows). d Release of the hydrolyzed nucleotides results in the extension of the myosin head permitting the sliding of the filaments (open arrows). ATP quickly rebinds to the ATP-binding site on the myosin head, allowing dissociation of the myosin away from the actin filament, and the cycle is repeated
Fig. 5
Fig. 5
Comparison of human and chick αMHC protein sequences. The human αMHC protein sequence (NP_002462) is compared to the chick sequence (NP_001013415), with various structural domains denoted on the human sequence [158]. The sequences were aligned in ClustalW2 [159, 160]. The nucleotide (ATP)-binding pocket is in part composed of P loop, Loop I, and Switch I with Switch II also important in its function. The rigid relay loop is proposed to connect the ATP binding site to the converter domain. The Strut and Loop 2 are regions that bind the upper and lower 50-kDa subdomains. Switch II is thought to be important in forming a kink, and allowing movement of the converter domain. The converter domain is a socket for the carboxy terminal helical tail and is where rotation occurs around the SH1 helix (also termed the “fulcrum” within the literature), allowing bending of the molecule. The proposed domains for the binding of titin and myosin binding protein-C (MyBP-C) are also denoted (underlined) [161, 162]. ELC essential light chain, RLC regulatory light chain, asterisk fully conserved residues, colon residues with strongly similar properties conserved; period residues with weakly similar properties conserved. Missense mutations previously described in the human MYH6 gene [2, 58, 59] and listed in Table 2 are denoted (boxed)
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