FKBP12 Binding Modulates Ryanodine Receptor Channel Gating

The ryanodine receptor (RyR1)/calcium release channel on the sarcoplasmic reticulum of skeletal muscle is comprised of four 565,000-dalton RyR1s, each of which binds one FK506 binding protein (FKBP12). RyR1 is required for excitation-contraction coupling in skeletal muscle. FKBP12, a cis-transpeptid...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-05, Vol.276 (20), p.16931-16935
Main Authors: Gaburjakova, Marta, Gaburjakova, Jana, Reiken, Steven, Huang, Fannie, Marx, Steven O., Rosemblit, Nora, Marks, Andrew R.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acid Substitution
Binding Sites
Caffeine - pharmacology
Cell Line
FK506-binding protein
Humans
Ion Channel Gating - physiology
Membrane Potentials - drug effects
Membrane Potentials - physiology
Microsomes - metabolism
Molecular Sequence Data
Muscle, Skeletal - physiology
Mutagenesis, Insertional
Mutagenesis, Site-Directed
Protein Binding
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
Ryanodine Receptor Calcium Release Channel - chemistry
Ryanodine Receptor Calcium Release Channel - genetics
Ryanodine Receptor Calcium Release Channel - physiology
Sarcoplasmic Reticulum - physiology
Tacrolimus Binding Protein 1A - metabolism
Transfection
Valine
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Summary:The ryanodine receptor (RyR1)/calcium release channel on the sarcoplasmic reticulum of skeletal muscle is comprised of four 565,000-dalton RyR1s, each of which binds one FK506 binding protein (FKBP12). RyR1 is required for excitation-contraction coupling in skeletal muscle. FKBP12, a cis-transpeptidyl-prolyl isomerase, is required for the normal gating of the RyR1 channel. In the absence of FKBP12, RyR1 channels exhibit increased gating frequency, suggesting that FKBP12 “stabilizes” the channel in the open and closed states. We now show that substitution of a Gly, Glu, or Ile for Val2461 in RyR1 prevents FKBP12 binding to RyR1, resulting in channels with increased gating frequency. In the case of the V2461I mutant RyR1, normal channel function can be restored by adding FKBP12.6, an isoform of FKBP12. These data identify Val2461 as a critical residue required for FKBP12 binding to RyR1 and demonstrate the functional role for FKBP12 in the RyR1 channel complex.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M100856200