Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives

The coordinated release of Ca2+ from the sarcoplasmic reticulum (SR) is critical for excitation-contraction coupling. This release is facilitated by ryanodine receptors (RyRs) that are embedded in the SR membrane. In skeletal muscle, activity of RyR1 is regulated by metabolites such as ATP, which up...

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Published in:Structure (London) 2023-07, Vol.31 (7), p.790-800.e4
Main Authors: Cholak, Spencer, Saville, James W., Zhu, Xing, Berezuk, Alison M., Tuttle, Katharine S., Haji-Ghassemi, Omid, Alvarado, Francisco J., Van Petegem, Filip, Subramaniam, Sriram
Format: Article
Language:English
Subjects:
Adenine - metabolism
Adenosine - metabolism
Adenosine Monophosphate - metabolism
Adenosine Triphosphate - metabolism
Animals
Calcium - metabolism
cryo-EM
Humans
Muscle, Skeletal - metabolism
nucleotide binding
Nucleotides - metabolism
Rabbits
Ryanodine Receptor
Ryanodine Receptor Calcium Release Channel - chemistry
RyR1
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Summary:The coordinated release of Ca2+ from the sarcoplasmic reticulum (SR) is critical for excitation-contraction coupling. This release is facilitated by ryanodine receptors (RyRs) that are embedded in the SR membrane. In skeletal muscle, activity of RyR1 is regulated by metabolites such as ATP, which upon binding increase channel open probability (Po). To obtain structural insights into the mechanism of RyR1 priming by ATP, we determined several cryo-EM structures of RyR1 bound individually to ATP-γ-S, ADP, AMP, adenosine, adenine, and cAMP. We demonstrate that adenine and adenosine bind RyR1, but AMP is the smallest ATP derivative capable of inducing long-range (>170 Å) structural rearrangements associated with channel activation, establishing a structural basis for key binding site interactions that are the threshold for triggering quaternary structural changes. Our finding that cAMP also induces these structural changes and results in increased channel opening suggests its potential role as an endogenous modulator of RyR1 conductance. [Display omitted] •Binding of AMP and larger nucleotide analogs induces global RyR1 structural changes•cAMP increases the proportion of open RyR1 channels•cAMP induces structural rearrangements associated with RyR1 channel activation Cholak et al. determined structures of RyR1 bound to ATP derivatives. ATP-γ-S, ADP, AMP, and cAMP induce structural rearrangements associated with channel activation, while adenine and adenosine bind the same pocket without inducing structural changes. Allosteric modulation and increased RyR1 channel opening with cAMP support its role as a RyR1 modulator.
ISSN:0969-2126
1878-4186
1878-4186
DOI:10.1016/j.str.2023.04.009