7ZRP

2.65 Angstrom crystal structure of Ca/CaM:CaMKIIdelta peptide complex

Summary for 7ZRP

• Entry DOI: 10.2210/pdb7zrp/pdb
• Descriptor: Calmodulin-1, Calcium/calmodulin-dependent protein kinase type II subunit delta, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: calcium-binding protein, calmodulin, cam, camkii, kinase, metal binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 39908.65

Authors

Helassa, N.,Antonyuk, S. (deposition date: 2022-05-04, release date: 2022-12-28, Last modification date: 2024-01-31)

Primary citation

Prakash, O.,Gupta, N.,Milburn, A.,McCormick, L.,Deugi, V.,Fisch, P.,Wyles, J.,Thomas, N.L.,Antonyuk, S.,Dart, C.,Helassa, N.
Calmodulin variant E140G associated with long QT syndrome impairs CaMKII delta autophosphorylation and L-type calcium channel inactivation.
J.Biol.Chem., 299:102777-102777, 2022

PubMed Abstract: Long QT syndrome (LQTS) is a human inherited heart condition that can cause life-threatening arrhythmia including sudden cardiac death. Mutations in the ubiquitous Ca-sensing protein calmodulin (CaM) are associated with LQTS, but the molecular mechanism by which these mutations lead to irregular heartbeats is not fully understood. Here, we use a multidisciplinary approach including protein biophysics, structural biology, confocal imaging, and patch-clamp electrophysiology to determine the effect of the disease-associated CaM mutation E140G on CaM structure and function. We present novel data showing that mutant-regulated CaMKIIδ kinase activity is impaired with a significant reduction in enzyme autophosphorylation rate. We report the first high-resolution crystal structure of a LQTS-associated CaM variant in complex with the CaMKIIδ peptide, which shows significant structural differences, compared to the WT complex. Furthermore, we demonstrate that the E140G mutation significantly disrupted Ca1.2 Ca/CaM-dependent inactivation, while cardiac ryanodine receptor (RyR2) activity remained unaffected. In addition, we show that the LQTS-associated mutation alters CaM's Ca-binding characteristics, secondary structure content, and interaction with key partners involved in excitation-contraction coupling (CaMKIIδ, Ca1.2, RyR2). In conclusion, LQTS-associated CaM mutation E140G severely impacts the structure-function relationship of CaM and its regulation of CaMKIIδ and Ca1.2. This provides a crucial insight into the molecular factors contributing to CaM-mediated arrhythmias with a central role for CaMKIIδ.

PubMed: 36496072
DOI: 10.1016/j.jbc.2022.102777

Experimental method

X-RAY DIFFRACTION (2.65 Å)