Loss of actomyosin regulation in distal arthrogryposis myopathy due to mutant myosin binding protein‐C slow

Abstract

Myosin binding protein C (MyBP-C) is expressed in striated muscles, where it plays key roles in the modulation of actomyosin cross-bridges. Slow MyBP-C (sMyBP-C) consists of multiple variants sharing common domains but also containing unique segments within the NH2 and COOH termini. Two missense mutations in the NH2 terminus (W236R) and COOH terminus (Y856H) of sMyBP-C have been causally linked to the development of distal arthrogryposis-1 (DA-1), a severe skeletal muscle disorder. Using a combination of in vitro binding and motility assays, we show that the COOH terminus mediates binding of sMyBP-C to thick filaments, while the NH2 terminus modulates the formation of actomyosin cross-bridges in a variant-specific manner. Consistent with this, a recombinant NH2-terminal peptide that excludes residues 34-59 reduces the sliding velocity of actin filaments past myosin heads from 9.0 ± 1.3 to 5.7 ± 1.0 μm/s at 0.1 μM, while a recombinant peptide that excludes residues 21-59 fails to do so. Notably, the actomyosin regulatory properties of sMyBP-C are completely abolished by the presence of the DA-1 mutations. In summary, our studies are the first to show that the NH2 and COOH termini of sMyBP-C have distinct functions, which are regulated by differential splicing, and are compromized by the presence of missense point mutations linked to muscle disease.

A Gain-of-Function Mutation in the M-domain of Cardiac Myosin-binding Protein-C Increases Binding to Actin

“…Notably, sequences encoding this tri-helix bundle are highly conserved across all isoforms of MyBP-C, suggesting that it meditates a common or conserved function in different muscle types. Consistent with this idea, skeletal muscle isoforms of myosin-binding protein C can exert similar effects as cardiac MyBP-C on actomyosin interactions in motility assays (22).…”

Orientation of Myosin Binding Protein C in the Cardiac Muscle Sarcomere Determined by Domain-Specific Immuno-EM

“…Taken together, the results suggest a similar organization for MyBP-C in both types of muscle. This is significant, given that skeletal MyBP-C, in addition to having less than 50% sequence identity with cMyBP-C, lacks a C0 domain and has different N-terminal interactions, phosphorylation capability, and actin and S2 binding propensity 3; 8; 65; 66 .…”

Thick Filament Protein Network, Functions, and Disease Association

“…The different sMyBP-C variants are coexpressed in variable amounts and combinations in both slow and fast-twitch skeletal muscles where they may coexist with fMyBP-C (11). However, there is no single mammalian muscle that expresses all known sMyBP-C proteins, which is indicative of their distinct structural and regulatory roles (7, 9–13). …”