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Lobe-dependent regulation of ryanodine receptor type 1 by calmodulin
Journal article   Open access   Peer reviewed

Lobe-dependent regulation of ryanodine receptor type 1 by calmodulin

Liang-Wen Xiong, Rhonda A Newman, George G Rodney, Oluwatoyin Thomas, Jia-Zheng Zhang, Anthony Persechini, Madeline A Shea and Susan L Hamilton
The Journal of biological chemistry, Vol.277(43), pp.40862-40870
10/25/2002
DOI: 10.1074/jbc.M206763200
PMID: 12185083
url
https://doi.org/10.1074/jbc.M206763200View
Published (Version of record) Open Access

Abstract

Calmodulin activates the skeletal muscle Ca(2+) release channel RYR1 at nm Ca(2+) concentrations and inhibits the channel at microm Ca(2+) concentrations. Using a deletion mutant of calmodulin, we demonstrate that amino acids 2-8 are required for high affinity binding of calmodulin to RYR1 at both nm and microm Ca(2+) concentrations and are required for maximum inhibition of the channel at microm Ca(2+) concentrations. In contrast, the addition of three amino acids to the N terminus of calmodulin increased the affinity for RYR1 at both nm and microm Ca(2+) concentrations, but destroyed its functional effects on RYR1 at nm Ca(2+). Using both full-length RYR1 and synthetic peptides, we demonstrate that the calmodulin-binding site on RYR1 is likely to be noncontiguous, with the C-terminal lobe of both apocalmodulin and Ca(2+)-calmodulin binding to amino acids between positions 3614 and 3643 and the N-terminal lobe binding at sites that are not proximal in the primary sequence. Ca(2+) binding to the C-terminal lobe of calmodulin converted it from an activator to an inhibitor, but an interaction with the N-terminal lobe was required for a maximum effect on RYR1. This interaction apparently depends on the native sequence or structure of the first few amino acids at the N terminus of calmodulin.
 Calmodulin - physiology Rabbits Animals Protein Structure, Secondary Electrophoresis, Polyacrylamide Gel Spectrometry, Fluorescence Muscle, Skeletal - metabolism Ryanodine Receptor Calcium Release Channel - metabolism Calmodulin - chemistry Ryanodine Receptor Calcium Release Channel - physiology

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