Structural insights into Ca(2+)-activated long-range allosteric channel gating of RyR1

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Physiology

Background:

• Ryanodine receptors (RyRs) are massive ion channels crucial for cellular calcium signaling.
• Their large cytoplasmic assembly suggests a long-range allosteric mechanism for regulation.
• Understanding RyR gating and selectivity is vital for cell function.

Purpose of the Study:

• To characterize the Ca(2+)-activated open-state structure of RyR1.
• To elucidate the long-range allosteric gating mechanism of RyRs.
• To uncover novel ion selectivity mechanisms in RyR1.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the RyR1 structure.
• High-resolution structural analysis (4.9 Å overall, 4.2 Å core).
• Comparison with the apo/closed-state structure.

Main Results:

• A Ca(2+)-activated open-state structure of RyR1 was determined.
• Evidence for long-range allosteric gating upon calcium activation was observed.
• Novel mechanisms for channel gating and ion selectivity were elucidated.

Conclusions:

• The study provides atomic-level insights into RyR1 channel gating and calcium regulation.
• Reveals a novel allosteric mechanism for RyR channel activation.
• Offers structural basis for gating and selectivity in six-transmembrane-helix cation channels.