Structural and Dynamic Characterization of the C313Y Mutation in Myostatin Dimeric Protein, Responsible for the “Double Muscle” Phenotype in Piedmontese Cattle

Abstract

The knowledge of the molecular effects of the C313Y mutation, responsible for the “double muscle” phenotype in Piedmontese cattle, can help understanding the actual mechanism of phenotype determination and paves the route for a better modulation of the positive effects of this economic important phenotype in the beef industry, while minimizing the negative side effects, now inevitably intersected. The structure and dynamic behavior of the active dimeric form of Myostatin in cattle was analyzed by means of three state-of-the-art Molecular Dynamics simulations, 200-ns long, of wild-type and C313Y mutants. Our results highlight a role for the conserved Arg333 in establishing a network of short and long range interactions between the two monomers in the wild-type protein that is destroyed upon the C313Y mutation even in a single monomer. Furthermore, the native protein shows an asymmetry in residue fluctuation that is absent in the double monomer mutant. Time window analysis on further 200-ns of simulation demonstrates that this is a characteristic behavior of the protein, likely dependent on long range communications between monomers. The same behavior, in fact, has already been observed in other mutated dimers. Finally, the mutation does not produce alterations in the secondary structure elements that compose the characteristic TGF-β cystine-knot motif.

Identification of a Novel Mutation in CTCF in a Family with MRD21

“…MD simulations have been shown to be successful in quantifying small changes in protein structures that can affect overall ligand binding. MD simulations have been applied widely and can facilitate understanding of the pathogenic mechanism of genetic mutations [50][51][52]. In our study, we con rmed that the novel missense mutation decreased CTCF binding a nity with DNA using MD simulations.…”

Missense mutations of NCPAG gene affect calving ease in Piedmontese cattle: preliminary evidences

“…One way could be to collect a sample population large enough to permit the detection of recombination between the SNPs and their consequences. Another way could consist on modelling the effects of the mutations by molecular dynamics (Bongiorni 2016). The latter method could also reveal if the effect on the trait is due indeed to the combination of the two SNPs as a haplotype.…”

Gene structure, recombinant expression and function characterization of Siniperca chuatsi Fsrp‐3

“…The homozygous disruption of the MSTN gene in mice was reported to be associated with reduction in body fat and a significant increase in skeletal muscle mass (Hill et al , ; Taylor et al , ). Cattle with naturally occurring MSTN mutations exhibit a similar double‐muscle phenotype (Bongiorni et al , ; Grobet et al , ; Kambadur et al , ), but inhibition of Mstn function in zebrafish Danio rerio Hamilton (1822) was not shown to result in significant increase in fibre numbers, suggesting that Mstn mainly affects muscle hypotrophy but not hyperplasia (Xu et al , ). Fsrp‐3 purified from serum was found to inhibit Mstn action (Hill et al , ).…”

“…FSRP‐3 is firstly discovered from mammal sera as a protein complex with MSTN, by which antagonize MSTN 's function (Hill et al , ). During muscle development, inactivation of MSTN results in notably increased muscle mass, this phenomenon commonly known as “double muscling” (Bongiorni et al , ; Rebhan & Funkenstein, ). Myogenesis is facilitated by four myogenic regulatory factors (MRF) including myf 5, myod , myog and mrf4 (Stern et al , ).…”