2vaf: Difference between revisions

caption="2vaf, resolution 3.8Å" />

'''CRYSTAL STRUCTURE OF HUMAN CARDIAC CALSEQUESTRIN'''<br />

==Overview==

Mutations of conserved residues of human cardiac calsequestrin (hCSQ2), a, high-capacity, low-affinity Ca(2+)-binding protein in the sarcoplasmic, reticulum, have been associated with catecholamine-induced polymorphic, ventricular tachycardia (CPVT). In order to understand the molecular, mechanism and pathophysiological link between these CPVT-related missense, mutations of hCSQ2 and the resulting arrhythmias, we generated three, CPVT-causing mutants of hCSQ2 (R33Q, L167H, and D307H) and two, non-pathological mutants (T66A and V76M) and investigated the effect of, these mutations. In addition, we determined the crystal structure of the, corresponding wild-type hCSQ2 to gain insight into the structural effects, of those mutations. Our data show clearly that all three CPVT-related, mutations lead to significant reduction in Ca(2+)-binding capacity in, spite of the similarity of their secondary structures to that of the, wild-type hCSQ2. Light-scattering experiments indicate that the, Ca(2+)-dependent monomer-polymer transitions of the mutants are quite, different, confirming that the linear polymerization behavior of CSQ is, linked directly to its high-capacity Ca(2+) binding. R33Q and D307H, mutations result in a monomer that appears to be unable to form a properly, oriented dimer. On the other hand, the L167H mutant has a disrupted, hydrophobic core in domain II, resulting in high molecular aggregates, which cannot respond to Ca(2+). Although one of the non-pathological, mutants, T66A, shares characteristics with the wild-type, the other null, mutant, V76M, shows significantly altered Ca(2+)-binding and, polymerization behaviors, calling for careful reconsideration of its, status.

==About this Structure==

==Reference==

[[Category: sarcoplasmic reticulum]]