de Windt, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands The locations of mutations on the ACTC protein correlated with the molecular effects in general, mutations in subdomain 3 affected the stability of the ACTC protein or affect the polymerization of actin filaments, while mutations in subdomains 1 and 4 more likely affect protein-protein interactions.Ĭitation: Mundia MM, Demers RW, Chow ML, Perieteanu AA, Dawson JF (2012) Subdomain Location of Mutations in Cardiac Actin Correlate with Type of Functional Change. Y166C actin had a higher critical concentration resulting in a lower Pi release rate due to reduced filament-forming potential. Increases to both the T m and DNase-I inhibition activity suggested interactions between E99K actin molecules under monomer-promoting conditions. Substitution of methionine for leucine at amino acid 305 showed no impact on the stability, nucleotide release rates, or DNase-I inhibition ability of the actin monomer however, during polymerization, a 2-fold increase in Pi release was observed. The R312H variant exhibited reduced stability, with a T m of 53.6☌ compared to 56.8☌ for WT actin, accompanied with increased polymerization critical concentration and Pi release rate, and a marked increase in nucleotide release rates. In general, the changes to the properties of the actin proteins themselves were subtle. Seven known cardiac actin mutants were expressed in a baculovirus system, and their intrinsic properties were studied. To understand the roles that the actin protein plays in the development of heart failure, we have taken a systematic approach toward characterizing human cardiac actin mutants that have been associated with either hypertrophic or dilated cardiomyopathy. Determining the molecular mechanisms that lead to the development of heart failure will help us gain better insight into the most costly health problem in the Western world.
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