Abstract
BackgroundMyosin performs ATP free energy transduction into mechanical work in the motor domain of the myosin heavy chain (MHC). Energy transduction is the definitive systemic feature of the myosin motor performed by coordinating in a time ordered sequence: ATP hydrolysis at the active site, actin affinity modulation at the actin binding site, and the lever-arm rotation of the power stroke. These functions are carried out by several conserved sub-domains within the motor domain. Single nucleotide polymorphisms (SNPs) affect the MHC sequence of many isoforms expressed in striated muscle, smooth muscle, and non-muscle tissue. The purpose of this work is to provide a rationale for using SNPs as a functional genomics tool to investigate structurefunction relationships in myosin. In particular, to discover SNP distribution over the conserved sub-domains and surmise what it implies about sub-domain stability and criticality in the energy transduction mechanism.ResultsAn automated routine identifying human nonsynonymous SNP amino acid missense substitutions for any MHC gene mined the NCBI SNP data base. The routine tested 22 MHC genes coding muscle and non-muscle isoforms and identified 89 missense mutation positions in the motor domain with 10 already implicated in heart disease and another 8 lacking sequence homology with a skeletal MHC isoform for which a crystallographic model is available. The remaining 71 SNP substitutions were found to be distributed over MHC with 22 falling outside identified functional sub-domains and 49 in or very near to myosin sub-domains assigned specific crucial functions in energy transduction. The latter includes the active site, the actin binding site, the rigid lever-arm, and regions facilitating their communication. Most MHC isoforms contained SNPs somewhere in the motor domain.ConclusionsSeveral functional-crucial sub-domains are infiltrated by a large number of SNP substitution sites suggesting these domains are engineered by evolution to be too-robust to be disturbed by otherwise intrusive sequence changes. Two functional sub-domains are SNP-free or relatively SNP-deficient but contain many disease implicated mutants. These sub-domains are apparently highly sensitive to any missense substitution suggesting they have failed to evolve a robust sequence paradigm for performing their function.
Highlights
Myosin performs ATP free energy transduction into mechanical work in the motor domain of the myosin heavy chain (MHC)
Functional impact based on: i) how well the native residue is conserved among isoforms, ii) comparison of general physical characteristics between the native and substituted side chain, and iii) the hypothetical role of the native residue in transduction and how this role could be Results Twenty-two human myosin heavy chain genes MYH1-4, MYH6-15, MYH7B, Myosin IE (MYOIE), MYO6, MYO7A and 7B, MYO9A and 9B, and MYO10 were searched for nonsynonymous Single nucleotide polymorphisms (SNPs) as described in METHODS
The embryonic isoform expresses in regenerating muscle and in extraocular muscles (EOM) [24]
Summary
Myosin performs ATP free energy transduction into mechanical work in the motor domain of the myosin heavy chain (MHC). For the purposes of this discussion, it is implicit that the SNPs accumulate in the genome because they negligibly affect survival, we recognize that some SNPs may have deleterious effects on the expression or function of protein products Another distinction that is germane to the present work is between synonymous and nonsynonymous SNPs. SNPs that lie within the coding region are synonymous if they do not change the amino acid specified by the codon and are nonsynonymous when they do. For less common SNPs, homozygous individuals that have two copies of the SNP are rare and deleterious consequences can often be masked by the presence of the more common functional allele Another factor in deciding the significance of the nonsynonymous SNPs is genetic redundancy. Our results are implications from the current data base that changes and grows daily
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