Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel | Dr Filip van Petegem

A manuscript by Dr. Filip van Petegem’s LSI research team was recently published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).

You can find the full publication here: Excerpts below.


Calmodulin is a ubiquitous Ca2+-sensing protein that can bind to more than a 100 different targets. In doing so, it endows many of these with Ca2+-dependent modulation. As one of the most conserved proteins throughout evolutionary history, all calmodulin genes in vertebrates are identical. However, several disease-associated mutations have been uncovered in human calmodulin genes, all of which are linked to inherited cardiac arrhythmia syndromes. This report shows high-resolution glimpses into calmodulin disease mutations and their effect on binding the L-type voltage-gated calcium channel, a channel involved in the cardiac action potential that receives calcium-dependent feedback. Although each mutant is able to affect calcium-dependent inactivation, the structures show that they adopt different mechanisms.


Calmodulin (CaM) represents one of the most conserved proteins among eukaryotes and is known to bind and modulate more than a 100 targets. Recently, several disease-associated mutations have been identified in the CALM genes that are causative of severe cardiac arrhythmia syndromes. Although several mutations have been shown to affect the function of various cardiac ion channels, direct structural insights into any CaM disease mutation have been lacking. Here we report a crystallographic and NMR investigation of several disease mutant CaMs, linked to long-QT syndrome, in complex with the IQ domain of the cardiac voltage-gated calcium channel (CaV1.2). Surprisingly, two mutants (D95V, N97I) cause a major distortion of the C-terminal lobe, resulting in a pathological conformation not reported before. These structural changes result in altered interactions with the CaV1.2 IQ domain. Another mutation (N97S) reduces the affinity for Ca2+ by introducing strain in EF hand 3. A fourth mutant (F141L) shows structural changes in the Ca2+-free state that increase the affinity for the IQ domain. These results thus show that different mechanisms underlie the ability of CaM disease mutations to affect Ca2+-dependent inactivation of the voltage-gated calcium channel.