Facilitated Cross-Bridge Interactions with Thin Filaments by Familial Hypertrophic Cardiomyopathy Mutations inα-Tropomyosin
| Autor: | Lisa A. Compton, Thomas M. Asbury, Justin R. Grubich, Ewa A. Bienkiewicz, Fang Wang, P. Bryant Chase, Goran Mihajlovic, Victor F. Miller, Nicolas M. Brunet |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Circular dichroism Article Subject lcsh:Biotechnology Health Toxicology and Mutagenesis Mutant lcsh:Medicine Cooperativity Tropomyosin Biology medicine.disease_cause Sarcomere Protein filament 03 medical and health sciences 0302 clinical medicine lcsh:TP248.13-248.65 Cardiomyopathy Hypertrophic Familial Genetics medicine Animals Humans Molecular Biology Actin 030304 developmental biology 0303 health sciences Mutation lcsh:R Myosin Subfragments Temperature General Medicine Molecular biology Actins Biophysics Molecular Medicine Calcium Electrophoresis Polyacrylamide Gel Rabbits 030217 neurology & neurosurgery Research Article Biotechnology |
| Zdroj: | Journal of Biomedicine and Biotechnology Journal of Biomedicine and Biotechnology, Vol 2011 (2011) |
| ISSN: | 1110-7251 1110-7243 |
| Popis: | Familial hypertrophic cardiomyopathy (FHC) is a disease of cardiac sarcomeres. To identify molecular mechanisms underlying FHC pathology, functional and structural differences in three FHC-related mutations in recombinantα-Tm (V95A, D175N, and E180G) were characterized using both conventional and modified in vitro motility assays and circular dichroism spectroscopy. Mutant Tm's exhibited reducedα-helical structure and increased unordered structure. When thin filaments were fully occupied by regulatory proteins, little or no motion was detected at pCa 9, and maximum speed (pCa 5) was similar for all tropomyosins. Ca2+-responsiveness of filament sliding speed was increased either by increasedpCa50(V95A), reduced cooperativityn(D175N), or both (E180G). When temperature was increased, thin filaments with E180G exhibited dysregulation at temperatures ~10°C lower, and much closer to body temperature, than WT. When HMM density was reduced, thin filaments with D175N required fewer motors to initiate sliding or achieve maximum sliding speed. |
| Databáze: | OpenAIRE |
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