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Myosin individualized: single nucleotide polymorphisms in energy transduction
Thomas P Burghardt1, Kevin L Neff, Eric D Wieben
1Department of Biochemistry and Molecular Biology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA. burghardt@mayo.edu
BMC Genomics
|March 16, 2010
Summary
Single nucleotide polymorphisms (SNPs) in myosin heavy chain (MHC) genes reveal insights into protein function. SNP distribution highlights robust, crucial sub-domains and sensitive areas, aiding structure-function studies.
Area of Science:
- Molecular Biology
- Genomics
- Biophysics
Background:
- Myosin heavy chain (MHC) motor domain performs ATP to mechanical work via coordinated functions.
- Conserved sub-domains within the MHC motor domain execute ATP hydrolysis, actin binding, and lever-arm rotation.
- Single nucleotide polymorphisms (SNPs) are common in MHC genes across various tissue types.
Purpose of the Study:
- To establish single nucleotide polymorphisms (SNPs) as a functional genomics tool for myosin structure-function investigations.
- To analyze SNP distribution across conserved MHC sub-domains.
- To infer sub-domain stability and criticality in myosin's energy transduction mechanism based on SNP patterns.
Main Methods:
- Automated mining of the NCBI SNP database for human nonsynonymous SNP amino acid missense substitutions in MHC genes.
- Testing of 22 MHC genes encoding muscle and non-muscle isoforms.
- Identification and distribution analysis of missense mutation positions within the MHC motor domain.
Main Results:
- Identified 89 missense mutation positions in the MHC motor domain across 22 genes.
- Found 49 SNP substitutions within or near crucial functional sub-domains (active site, actin binding site, lever-arm).
- Observed that most MHC isoforms contain SNPs in the motor domain.
Conclusions:
- Highly substituted functional sub-domains suggest evolutionary robustness against sequence changes.
- SNP-deficient sub-domains with disease-implicated mutants indicate high sensitivity to missense substitutions.
- SNP analysis provides a framework for understanding myosin sub-domain roles in energy transduction.
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