D. Szczesna et al., Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation, J BIOL CHEM, 276(10), 2001, pp. 7086-7092
The effect of the familial hypertrophic cardiomyopathy mutations, A13T, F18
L, E22K, R58Q, and P95A, found in the regulatory light chains of human card
iac myosin has been investigated. The results demonstrate that E22K and R58
Q, located in the immediate extension of the helices flanking the regulator
y light chain Ca2+ binding site, had dramatically altered Ca2+ binding prop
erties. The K-Ca value for E22K was decreased by similar to 17-fold compare
d with the wild-type light chain, and the R58Q mutant did not bind Ca2+. In
terestingly, Ca2+ binding to the R58Q mutant was restored upon phosphorylat
ion, whereas the E22K mutant could not be phosphorylated, In addition, the
alpha -helical content of phosphorylated R58Q greatly increased with Ca2+ b
inding. The A13T mutation, located near the phosphorylation site (Ser-15) o
f the human cardiac regulatory light chain, had 3-fold lower K-Ca than wild
-type light chain, whereas phosphorylation of this mutant increased the Ca2
+ affinity 6-fold. Whereas phosphorylation of wildtype light chain decrease
d its Ca2+ affinity, the opposite was true for A13T. The alpha -helical con
tent of the A13T mutant returned to the level of wild-type light chain upon
phosphorylation, The phosphorylation and Ca2+ binding properties of the re
gulatory light chain of human cardiac myosin are important for physiologica
l function, and alteration any of these could contribute to the development
of hypertrophic cardiomyopathy.