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Research Themes Drug discovery

Ryanodine Receptor

SBKB [doi:10.3942/psi_sgkb/fm_2015_4]
Featured System - April 2015
Short description: PSI researchers take a close look at a gated calcium channel that controls muscle contraction.

Calcium is used to control many cellular processes that require synchronized action. For instance, in muscle cells, large quantities of calcium are stored in special compartments, termed the sarcoplasmic reticulum, which is released in a flood to trigger contraction simultaneously throughout the cell. The ryanodine receptor is at the center of this process. It forms a gated channel through the membrane of these storage compartments, which opens and releases the calcium when triggered.

Gating Machinery

The ryanodine receptor, shown here from PDB entry 3j8e, is a huge molecular complex with many functional parts. It is composed of four large protein chains, shown here in blue. In the center of the complex, all four chains come together to form the gated channel through the membrane (shown here at the bottom). On the cytoplasmic side of the membrane (at the top here), the chains fold into an elaborate structure that interacts with many proteins that regulate and control opening of the channel. For instance, this structure includes the small protein calstabin2 (also known as FKBP12.6, shown here in green) that stabilizes the closed form of the channel.

Open and Shut Case

As with many proteins involved in muscle contraction, the ryanodine receptor is a sensitive target for poisons. It is named after the poisonous alkaloid ryanodine, which locks the channel shut and causes paralysis. Scientists are currently looking for less drastic ways to modulate the opening and closing of ryanodine receptors, for use as therapeutic drugs, since disfunction of these receptors plays a role in diseases like heart failure and cardiac arrhythmia.


Revealing the Protein Fold

The ryanodine receptor has proven to be a challenging target for structural study, given its large size and flexible nature, but several groups have been able to obtain near-atomic structures using electron microscopy. The electron density map shown here was generated by PSI researchers at NYCOMPS with a resolution that is sufficient to identify the major structural elements of the complex. The image is colored by the effective resolution of different parts of the map, which is highest at the central channel (in blue, at about 4 Angstroms resolution) and gets slightly fuzzier at the edges (in red, at about 6 Angstroms resolution).

Sensing Calcium

The ryanodine receptor is triggered to open by two processes. Many are often associated with voltage-gated calcium channels that interact directly with the ryanodine receptor when they receive the signal to open. In addition, the ryanodine receptor senses the level of calcium outside the storage compartment, and if levels rise, they also open, allowing even more calcium to pass through. The structure of the receptor has revealed a putative calcium-binding domain, shown here in magenta. It is some distance from the channel (shown in red). PSI researchers have identified several interactions between the channel-forming portions of the receptor and the cytoplasmic portions, which may be important for transmitting the signal. To explore these in more detail, the JSmol tab below displays an interactive JSmol.

Ryanodine Receptor (PDB entry 3j8e)

Four helices, one from each chain, form the central channel of the ryanodine receptor (shown here in red). A conserved glycine amino acid (shown in white) forms a kink in the middle of this helix and may be important for the opening and closing of the channel. The putative calcium-sensing module, shown in magenta, is a distance away from the channel. Several interactions between the membrane-crossing portions of the channel and the large cytoplasmic portion may be important for linking calcium binding to channel opening. Use the buttons to display these. They include a large loop between the membrane-crossing helices S2 and S3, and a tight interaction of the C-terminal extension of the main channel helix with a domain from the cytoplasmic portion.

References

  1. 4uwe: Efremov, R. G., Leitner, A., Aebersold, R. & Raunser, S. Architecture and conformational switch mechanism of the ryanodine receptor. Nature 517, 39-43 (2015).

  2. 3j6h: Yan, Z. et al. Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution. Nature 517, 50-55 (2015).

  3. 3j8e: Zalk, R. et al. Structure of a mammalian ryanodine receptor. Nature 517, 44-49 (2015).

  4. Zalk, R., Lehnart, S. E. & Marks, A. R. Modulation of the ryanodine receptor and intracellular calcium. Annu. Rev. Biochem. 76, 367-385 (2007).

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