Membrane protein folding has been captured for the first time in 3D and at a single-atom level

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Proteins twist and contort as they go about their work. And now scientists have found a way to film these nuanced movements, as reported 23 December in the journal Science.

In research conducted at SACLA, Japan’s XFEL (X-ray free electron laser) facility, membrane protein folding has been captured for the first time in 3D and at a single-atom level.

Membrane proteins are popular drug targets, as they are exposed to the environment surrounding the cell. Capturing their movements on video, the authors say, is potentially a revolutionary step forward in drug development.

Lead author Eriko Nango of Kyoto University explains that, whereas conventional X-ray crystallography only captures static protein structures, SACLA has enabled the team to observe minute changes in protein structures during transformation.

“With XFEL, we can get diffraction images of protein structures using crystals that are merely a few micrometers in size. SACLA’s laser pulses are extremely short, lasting less than 10 femtoseconds, exposing the protein crystals to minimal radiation damage,” says Nango.

The technique enabled the team to observe proteins before deformation from radiation, and also take ‘snapshots’ in time increments shorter than previously possible, later assembling these into time-lapse movies.

Nango elaborates, “It’s like being able to add extra pages to a flip book animation, so that you don’t lose track of very fine, detailed movements.”

In the study, the team observed bacteriorhodopsin, a membrane protein of microorganisms that live in hyper-salty conditions.

“Bacteriorhodopsin releases hydrogen ions — essentially protons — outside the cell in response to light,” says corresponding author So Iwata of Kyoto University. “The movement of these protons is always one-way. How it’s pumped out of the cell, but not back in, has puzzled scientists for fifty years.”

The team designed a device to shine lasers in the range of visible light, in order to capture bacteriorhodopsin’s reactions immediately after light exposure.

In 13 images taken between one nanosecond and one millisecond after irradiation, the researchers found that bacteriorhodopsin goes through four transformations before returning to its default form. As the protein reshapes, amino acid residues in its vicinity move toward the inside of the cell, being replaced by water molecules that pass protons to amino acid residues in the cell’s exterior.

“Membrane transport proteins are everywhere in biology,” continues Iwata. “This new experimental method is a game-changer for research in the life sciences, because we can now investigate protein structures, including their motion, in much greater detail.”