Journal
BIOCHEMICAL JOURNAL
Volume 401, Issue -, Pages 333-339Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20060902
Keywords
domain-domain interaction; excitation-contraction coupling; malignant hyperthermia; ryanodine receptor
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Funding
- NHLBI NIH HHS [HL072841, R01 HL072841] Funding Source: Medline
- NIAMS NIH HHS [R01 AR016922, AR 16922] Funding Source: Medline
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To explain the mechanism of pathogenesis of channel disorder in MH (malignant hyperthermia), we have proposed a model in which tight interactions between the N-terminal and central domains of RyR1 (ryanodine receptor 1) stabilize the closed state of the channel, but mutation in these domains weakens the inter-domain interaction and destabilizes the channel. DP4 (domain peptide 4), a peptide corresponding to residues Leu(2442)-Pro(2477) of the central domain, also weakens the domain interaction and produces MH-like channel destabilization, whereas an MH mutation (R2458C) in DP4 abolishes these effects. Thus DP4 and its mutants serve as excellent tools for structure-function studies. Other MH mutations have been reported in the literature involving three other amino acid residues in the DP4 region (Arg(24), Iie(2453) and Arg(2454)). In the present paper we investigated the activity of several mutants of DP4 at these three residues. The ability to activate ryanodine binding or to effect Car(2+) release was severely diminished for each of the Mill mutants. Other substitutions were less effective. Structural studies, using NMR analysis, revealed that the preptide has two a-helical regions. It is apparent that the MH mutations are clustered at the C-terminal end of the first helix. The data in the present paper indicates that mutation of residues in this region disrupts the interdomain interactions that stabilize the closed state of the channel.
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