Abstract
Point mutations in cardiac myosin, the heart's molecular motor, produce
distinct clinical phenotypes: hypertrophic (HCM) and dilated (DCM)
cardiomyopathy. Do mutations alter myosin's molecular mechanics in
a manner that is predictive of the clinical outcome? We have directly
characterized the maximal force-generating capacity (F(max)) of two
HCM (R403Q, R453C) and two DCM (S532P, F764L) mutant myosins isolated
from homozygous mouse models using a novel load-clamped laser trap
assay. F(max) was 50% (R403Q) and 80% (R453C) greater for the HCM
mutants compared with the wild type, whereas F(max) was severely
depressed for one of the DCM mutants (65% S532P). Although F(max)
was normal for the F764L DCM mutant, its actin-activated ATPase activity
and actin filament velocity (V(actin)) in a motility assay were significantly
reduced (Schmitt JP, Debold EP, Ahmad F, Armstrong A, Frederico A,
Conner DA, Mende U, Lohse MJ, Warshaw D, Seidman CE, Seidman JG.
Proc Natl Acad Sci USA 103: 14525-14530, 2006.). These F(max) data
combined with previous V(actin) measurements suggest that HCM and
DCM result from alterations to one or more of myosin's fundamental
mechanical properties, with HCM-causing mutations leading to enhanced
but DCM-causing mutations leading to depressed function. These mutation-specific
changes in mechanical properties must initiate distinct signaling
cascades that ultimately lead to the disparate phenotypic responses
observed in HCM and DCM.
Links and resources
Tags