Malignant hyperthermia mutation sites in the Leu(2442)-Pro(2477) (DP4) region of RyR1 (ryanodine receptor 1) are clustered in a structurally and functionally definable area

Date

2007

Authors

Bannister, Mark L
Hamada, Tomoyo
Murayama, Takashi
Harvey, Peta
Casarotto, Marco
Dulhunty, Angela
Ikemoto, Noriaki

Journal Title

Journal ISSN

Volume Title

Publisher

Portland Press

Abstract

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 (Arg 2452, 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.

Description

Keywords

Keywords: Molecular structure; Pathology; Proteins; Domain-domain interaction; Excitation-contraction coupling; Malignant hyperthermia; Ryanodine receptor; Mutagenesis; arginine; isoleucine; leucine; proline; ryanodine receptor 1; alpha helix; amino terminal sequen Domain-domain interaction; Excitation-contraction coupling; Malignant hyperthermia; Ryanodine receptor

Citation

Source

Biochemical Journal

Type

Journal article

Book Title

Entity type

Access Statement

License Rights

DOI

10.1042/BJ20060902

Restricted until

2037-12-31