β Strand Switching: A Novel Structural Rescue Mechanism in a Δexon3 Cardiac Ryanodine Receptor Mutant

The contraction of cardiac muscle requires release of Ca2+ from the sarcoplasmic reticulum through the cardiac ryanodine receptor (RyR2). Several mutations in RyR2 are linked to inherited disorders, including triggered cardiac arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT) that may lead to sudden cardiac death. A severe form of CPVT is caused by removal of an entire third exon (Δexon3) of RyR2. The 35 deleted residues form secondary structure elements which are crucial in folding of the N-terminal domain, raising the question of why the deletion is neither lethal nor confers a loss-of-function phenotype. A 2.3A crystal structure shows that the removal results in a structural rescue: an otherwise flexible loop compensates for the loss by inserting itself into the β trefoil domain and increases the thermal stability. The other β strands in the domain show increased mobility to accommodate a sequence that bears no similarity to the deleted exon. The exon3 deletion is not tolerated in the corresponding RyR1 domain. The rescue shows a novel mechanism by which RyR2 channels can adjust their Ca2+ release properties through altering the structure of an individual domain.