6XXX

1.25 Angstrom crystal structure of Ca/CaM A102V:RyR2 peptide complex

This is a non-PDB format compatible entry.

Summary for 6XXX

• Entry DOI: 10.2210/pdb6xxx/pdb
• Related: 6XXF
• Descriptor: Calmodulin-1, LYS-LYS-ALA-VAL-TRP-HIS-LYS-LEU-LEU-SER-LYS-GLN-ARG-LYS-ARG-ALA-VAL-VAL-ALA-CYS-PHE, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: calcium-binding protein, cardiac muscle contraction, ryr2, metal binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 19546.03

Authors

Antonyuk, S.,Helassa, N. (deposition date: 2020-01-28, release date: 2021-02-10, Last modification date: 2024-01-24)

Primary citation

Prakash, O.,Held, M.,McCormick, L.F.,Gupta, N.,Lian, L.Y.,Antonyuk, S.,Haynes, L.P.,Thomas, N.L.,Helassa, N.
CPVT-associated calmodulin variants N53I and A102V dysregulate Ca2+ signalling via different mechanisms.
J.Cell.Sci., 135:-, 2022

PubMed Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited condition that can cause fatal cardiac arrhythmia. Human mutations in the Ca2+ sensor calmodulin (CaM) have been associated with CPVT susceptibility, suggesting that CaM dysfunction is a key driver of the disease. However, the detailed molecular mechanism remains unclear. Focusing on the interaction with the cardiac ryanodine receptor (RyR2), we determined the effect of CPVT-associated variants N53I and A102V on the structural characteristics of CaM and on Ca2+ fluxes in live cells. We provide novel data showing that interaction of both Ca2+/CaM-N53I and Ca2+/CaM-A102V with the RyR2 binding domain is decreased. Ca2+/CaM-RyR23583-3603 high-resolution crystal structures highlight subtle conformational changes for the N53I variant, with A102V being similar to wild type (WT). We show that co-expression of CaM-N53I or CaM-A102V with RyR2 in HEK293 cells significantly increased the duration of Ca2+ events; CaM-A102V exhibited a lower frequency of Ca2+ oscillations. In addition, we show that CaMKIIδ (also known as CAMK2D) phosphorylation activity is increased for A102V, compared to CaM-WT. This paper provides novel insight into the molecular mechanisms of CPVT-associated CaM variants and will facilitate the development of strategies for future therapies.

PubMed: 34888671
DOI: 10.1242/jcs.258796

Experimental method

X-RAY DIFFRACTION (1.25 Å)