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FKBP12.6 activates RyR1 : investigating the amino acid residues critical for channel modulation

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venturi2014biophysj824.pdf (1.558Mb)
Date
18/02/2014
Author
Venturi, Elisa
Galfre, Elena
O'Brien, Fiona
Pitt, Samantha J.
Bellamy, Stuart
Sessions, Richard B.
Sitsapesan, Rebecca
Keywords
Calcium-release channel
Cardiac ryanodine receptor
Muscle sarcoplasmic-reticulum
Skeletal-muscle
FK506-binding protein
Heart-failure
Defective regulation
Selective binding
Cytoplasmic ca2+
Leak
QD Chemistry
QH301 Biology
Metadata
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Abstract
We have previously shown that FKBP12 associates with RyR2 in cardiac muscle and that it modulates RyR2 function differently to FKBP12.6. We now investigate how these proteins affect the single-channel behavior of RyR1 derived from rabbit skeletal muscle. Our results show that FKBP12.6 activates and FKBP12 inhibits RyR1. It is likely that both proteins compete for the same binding sites on RyR1 because channels that are preactivated by FKBP12.6 cannot be subsequently inhibited by FKBP12. We produced a mutant FKBP12 molecule (FKBP12(E31Q/D32N/W59F)) where the residues Glu(31), Asp(32), and Trp(59) were converted to the corresponding residues in FKBP12.6. With respect to the functional regulation of RyR1 and RyR2, the FKBP12(E31Q/D32N/W59F) mutant lost all ability to behave like FKBP12 and instead behaved like FKBP12.6. FKBP12(E31Q/D32N/W59F) activated RyR1 but was not capable of activating RyR2. In conclusion, FKBP12.6 activates RyR1, whereas FKBP12 activates RyR2 and this selective activator phenotype is determined within the amino acid residues Glu31, Asp(32), and Trp(59) in FKBP12 and Gln(31), Asn(32), and Phe(59) in FKBP12.6. The opposing but different effects of FKBP12 and FKBP12.6 on RyR1 and RyR2 channel gating provide scope for diversity of regulation in different tissues.
Citation
Venturi , E , Galfre , E , O'Brien , F , Pitt , S J , Bellamy , S , Sessions , R B & Sitsapesan , R 2014 , ' FKBP12.6 activates RyR1 : investigating the amino acid residues critical for channel modulation ' Biophysical Journal , vol 106 , no. 4 , pp. 824-833 . DOI: 10.1016/j.bpj.2013.12.041
Publication
Biophysical Journal
Status
Peer reviewed
DOI
http://dx.doi.org/10.1016/j.bpj.2013.12.041
ISSN
0006-3495
Type
Journal article
Rights
© The Authors. This is an Open Access article distributed under the terms of the Creative Commons-Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/2.0/), which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Description
Funding: British Heart Foundation
Collections
  • Biomedical Sciences Research Complex (BSRC) Research
  • University of St Andrews Research
  • Medicine Research
URI
http://hdl.handle.net/10023/4794

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