Dr. David Heeley - February 11, 2019

The Role of the Myosin Essential Light Chain and an update on Myosin

Myosin II (muscle) is a hexamer. Two smaller subunits (one essential light chain and one regulatory light chain) bind to the lever arm section of each heavy chain. In fast skeletal muscle, there are equal amounts of two variants of the essential light chain, A1 and A2. They are of identical sequence except for an amino-terminal extension in A1 (absent in A2) that is enriched in alanine and proline (~ 50% of composition). By comparison, slow skeletal muscle myosin contains A1 and the regulatory light chain. That is it lacks the shorter light chain (A2).

Head fragments composed of either essential light chain were prepared from fast muscle myosin and analyzed biochemically. The N-t extension (~ 40 amino acids in rodent) increases the actin affinity of the head. This second site of actin attachment to slows down steps in the actomyosin kinetic cycle (Ref 1).

Other news: In the healthy heart a portion of the myosin pool exists in an autoinhibited (folded) state, referred to as super-relaxed myosin (Ref. 2). Mutations in the cardiac myosin heavy chain destabilize the folded state leading to hyper-contractility, ventricular wall thickening and a loss of compliance. Mavacamten is a small molecule currently in phase three clinical trials that is reported to stabilize the folded state and throttle back the heart (Ref. 3 and 4).

References

(1) Heeley and White (manuscript in preparation). Investigation of the effect of essential light chain on actomyosin kinetics.

(2) Hooijman et al (2011) Biophys J 100, 1969 – 1976. A new state of cardiac myosin with very slow ATP turnover: a potential cardioprotective mechanism in the heart.

(3) Rohde et al (2018) Proc. Natl. Acad. Sci. 115, E7486-E7494. Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin.

(4) Anderson et al (2018) Proc. Natl. Acad. Sci. 115, E8143–E8152. Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers.

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