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Structure of Calmodulin Bound to the Cardiac Ryanodine Receptor (RyR2) at Residues: Phe4246 to Val4271
Structural highlights
DiseaseCALM1_HUMAN The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of LQT14. FunctionCALM1_HUMAN Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).[1] [2] [3] [4] Publication Abstract from PubMedCalmodulin (CaM) regulates the activity of a Ca(2+) channel known as the cardiac ryanodine receptor (RyR2), which facilitates the release of Ca(2+) from the sarcoplasmic reticulum during excitation-contraction coupling in cardiomyocytes. Mutations that disrupt this CaM-dependent channel inactivation result in cardiac arrhythmias. RyR2 contains three different CaM binding sites: CaMBD1 (residues 1940-1965), CaMBD2 (residues 3580-3611), and CaMBD3 (residues 4246-4275). Here, we report a crystal structure of Ca(2+)-bound CaM bound to RyR2 CaMBD3. The structure reveals Ca(2+) bound to the four EF-hands of CaM as well as a fifth Ca(2+) bound to CaM in the interdomain linker region involving Asp81 and Glu85. The CaM mutant E85A abolishes the binding of the fifth Ca(2+) and weakens the binding of CaMBD3 to Ca(2+)-bound CaM. Thus, the binding of the fifth Ca(2+) is important for stabilizing the complex in solution and is not a crystalline artifact. The CaMBD3 peptide in the complex adopts an alpha-helix (between Phe4246 and Val4271) that interacts with both lobes of CaM. Hydrophobic residues in the CaMBD3 helix (Leu4255 and Leu4259) form intermolecular contacts with the CaM N-lobe, and the CaMBD3 mutations (L4255A and L4259A) each weaken the binding of CaM to RyR2. Aromatic residues on the opposite side of the CaMBD3 helix (Phe4246 and Tyr4250) interact with the CaM C-lobe, but the mutants (F4246A and Y4250A) have no detectable effect on CaM binding in solution. We suggest that the binding of CaM to CaMBD3 and the binding of a fifth Ca(2+) to CaM may contribute to the regulation of RyR2 channel function. The Crystal Structure of Calmodulin Bound to the Cardiac Ryanodine Receptor (RyR2) at Residues Phe4246-Val4271 Reveals a Fifth Calcium Binding Site.,Yu Q, Anderson DE, Kaur R, Fisher AJ, Ames JB Biochemistry. 2021 Apr 13;60(14):1088-1096. doi: 10.1021/acs.biochem.1c00152. , Epub 2021 Mar 23. PMID:33754699[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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