First sightings of individual proteins as they fold

Proteins, it appears, have taken Frank Sinatra’s “I Did It My Way” close to heart. A new study published in the current issue of Proceedings of the National Academy of Sciences (PNAS) reveals how single proteins, each a few nanometers (billionths of a meter) long, fold to assume their final shape. It shows that even proteins having the same final shape achieve it by taking different routes.

Proteins are the fundamental components of all living cells. They start out as randomly shaped chains of amino acids and twist into a well-defined three-dimensional structure that determines their function. When this process goes awry, it can result in a wide variety of disorders, including some cancers.

For decades, scientists have pondered how proteins fold. The answer, it was long believed, could be obtained only through watching the folding process of individual proteins. Yet this presented a huge challenge since proteins are extremely small and constantly on the go.

Using a novel technology developed in their lab, a group of scientists headed by Dr. Gilad Haran of the Weizmann Institute’s Chemical Physics Department took the first glimpses of single proteins in the act of folding. The proteins fold cautiously, in stages. They make decisions along the way, taking into account decisions made during earlier folding stages, their environment, and their own condition. The results verify what theoretical scientists have suspected for nearly a decade – that protein molecules vary in the routes they take to the same folded shape and form numerous intermediate shapes on the road. The belief that had prevailed earlier was that one distinct route would dictate each shape.

In the past, scientists had tried to pin proteins down to get a steady look at them, but this often changed their properties. The technology that made it possible to view the proteins, previously published by the Weizmann team, is a unique “protein safari.” The scientists’ solution was to trap the proteins in vesicles where they could move about freely, unaware of scientist-made borders. These vesicles, composed of lipids (the same materials that form the membranes of living cells), are 100 nanometers wide. Thus, they are much larger than the proteins yet narrow enough to be fully lit by a tightly focused laser beam (which is around 300 nanometers wide). They are attached to a clean glass surface, making their contents easy to view over long periods of time.

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Dr. Gilad Haran’s research is supported by the Avron-Wilstaetter Minerva Center for Research in Photosynthesis, Fritz Haber Center for Physical Chemistry and Clore Center for Biological Physics. Dr. Haran is the incumbent of the Benjamin H. Swig and Jack D. Weiler Career Development Chair.