Summary for 2VAF
| Entry DOI | 10.2210/pdb2vaf/pdb |
| Descriptor | CALSEQUESTRIN-2 (1 entity in total) |
| Functional Keywords | calcium, glycoprotein, polymorphism, muscle protein, disease mutation, sarcoplasmic reticulum, crystal structure human cardiac calsequestrin, metal-binding protein, metal binding protein |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 1 |
| Total formula weight | 43997.59 |
| Authors | Kim, E.,Youn, B.,Kemper, L.,Campbell, C.,Milting, H.,Varsanyi, M.,Kang, C. (deposition date: 2007-08-31, release date: 2007-09-11, Last modification date: 2023-12-13) |
| Primary citation | Kim, E.,Youn, B.,Kemper, L.,Campbell, C.,Milting, H.,Varsanyi, M.,Kang, C. Characterization of Human Cardiac Calsequestrin and its Deleterious Mutants. J.Mol.Biol., 373:1047-, 2007 Cited by PubMed Abstract: Mutations of conserved residues of human cardiac calsequestrin (hCSQ2), a high-capacity, low-affinity Ca2+-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 Ca2+-binding capacity in spite of the similarity of their secondary structures to that of the wild-type hCSQ2. Light-scattering experiments indicate that the Ca2+-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 Ca2+ 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 Ca2+. Although one of the non-pathological mutants, T66A, shares characteristics with the wild-type, the other null mutant, V76M, shows significantly altered Ca2+-binding and polymerization behaviors, calling for careful reconsideration of its status. PubMed: 17881003DOI: 10.1016/J.JMB.2007.08.055 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.8 Å) |
Structure validation
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