This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Every step we take begins with a burst of calcium inside our muscle cells, causing them to contract. To prepare for action, the cells keep calcium locked in an internal compartment, the sarcoplasmic reticulum.
Studding its membrane are thousands of RyR1 channels—the largest known ion channels—that contain pores that release the calcium. For a muscle to contract properly, RyR1 channels must open synchronously via a mechanism known as "coupled gating." How they accomplish this has been unclear since it was described almost 30 years ago. Vasilii Mikirtumov, a former doctoral student in the In Situ Structural Biology Lab of Dr.
Misha Kudryashev at the Max Delbrück Center, has now captured the first high-resolution 3D images of RyR1 at six stages of opening inside the intact sarcoplasmic reticulum membrane. The work is published in Nature Communications. Although the structure of RyR1 has been described before, previous studies used channels that had been removed from the membrane.
Instead, the Kudryashev lab studied the structure of RyR1 in its natural environment using the advanced imaging techniques of cryo-electron microscopy and tomography. "Because RyR1 is a membrane protein, you have to pull it out with detergents to purify it. But that environment can be disruptive to such a sensitive protein," says Mikirtumov, who is now a postdoctoral researcher in the lab of Christian Spahn at Charité – Universitätsmedizin Berlin.
"We wanted to capture the structure of the channel in its native membrane and find out whether its opening mechanism looks different there." The researchers found that it does. The images show that neighboring channels remain in contact with each other when transitioning from the closed to open states. This contact, or interface, mediates coupled gating: As one channel rotates open, it strains the interface with its neighbor, making it easier for that channel to rotate and open too.
"It's like the cogs in a clock," says Kudryashev, senior author of the paper. "Once one cog turns, it primes its neighbors to turn, too." The team isolated the sarcoplasmic reticulum from rabbit muscle and imaged it at the Core Facility for Cryo-Electron Microscopy, which is run jointly by Charité – Universitätsmedizin Berlin, the Max Delbrück Center and the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP). The Kudryashev lab has specialized expertise in cryo-electron microscopy and tomography and the computational tools necessary to analyze the resulting data.
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