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 interdomain interaction and destabilizes the channel. DP4 (domain peptide 4), a peptide corresponding to residues Leu2442–Pro2477 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 (Arg2452, Ile2453 and Arg2454). 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 Ca2+ release was severely diminished for each of the MH mutants. Other substitutions were less effective. Structural studies, using NMR analysis, revealed that the peptide has two α-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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Research Article|
December 11 2006
Malignant hyperthermia mutation sites in the Leu2442–Pro2477 (DP4) region of RyR1 (ryanodine receptor 1) are clustered in a structurally and functionally definable area
Mark L. Bannister
;
Mark L. Bannister
*
Boston Biomedical Research Institute, Watertown, MA 02472, U.S.A.
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Tomoyo Hamada
;
Tomoyo Hamada
*
Boston Biomedical Research Institute, Watertown, MA 02472, U.S.A.
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Takashi Murayama
;
Takashi Murayama
†
Department of Pharmacology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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Peta J. Harvey
;
Peta J. Harvey
‡
Division of Molecular Bioscience, John Curtin School of Medical Research, P.O. Box 334, Australian National University, Canberra, ACT 2601, Australia
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Marco G. Casarotto
;
Marco G. Casarotto
‡
Division of Molecular Bioscience, John Curtin School of Medical Research, P.O. Box 334, Australian National University, Canberra, ACT 2601, Australia
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Angela F. Dulhunty
;
Angela F. Dulhunty
‡
Division of Molecular Bioscience, John Curtin School of Medical Research, P.O. Box 334, Australian National University, Canberra, ACT 2601, Australia
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Noriaki Ikemoto
Noriaki Ikemoto
1
*
Boston Biomedical Research Institute, Watertown, MA 02472, U.S.A.§
Department of Neurology, Harvard Medical School, Boston, MA 02115, U.S.A.1
To whom correspondence should be addressed (email ikemoto@bbri.org).
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Biochem J (2007) 401 (1): 333-339.
Article history
Received:
June 14 2006
Revision Received:
July 25 2006
Accepted:
September 07 2006
Accepted Manuscript online:
September 07 2006
Citation
Mark L. Bannister, Tomoyo Hamada, Takashi Murayama, Peta J. Harvey, Marco G. Casarotto, Angela F. Dulhunty, Noriaki Ikemoto; Malignant hyperthermia mutation sites in the Leu2442–Pro2477 (DP4) region of RyR1 (ryanodine receptor 1) are clustered in a structurally and functionally definable area. Biochem J 1 January 2007; 401 (1): 333–339. doi: https://doi.org/10.1042/BJ20060902
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