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The Path To A Folded Protein, Long A Subject Of Debate, Appears In Many Cases To Be Long And Winding

Date:
February 27, 2002
Source:
University Of Pennsylvania
Summary:
It’s a long-simmering debate in the world of physical chemistry: Does the folding of proteins into biologically active shapes better resemble a luge run – fast, linear and predictable – or the more freeform trajectories of a ski slope? New research from the University of Pennsylvania offers the strongest evidence yet that proteins shimmy into their characteristic shapes not via a single, unyielding route but by paths as individualistic as those followed by skiers coursing from a mountain summit down to the base lodge.

PHILADELPHIA – It’s a long-simmering debate in the world of physical chemistry: Does the folding of proteins into biologically active shapes better resemble a luge run – fast, linear and predictable – or the more freeform trajectories of a ski slope? New research from the University of Pennsylvania offers the strongest evidence yet that proteins shimmy into their characteristic shapes not via a single, unyielding route but by paths as individualistic as those followed by skiers coursing from a mountain summit down to the base lodge. The new support for a more heterogeneous model of protein folding comes in a paper published today on the Web site of the Proceedings of the National Academy of Sciences.

"The traditional view has been that a protein passes through a series of fixed reactions to reach its folded state," said senior author Feng Gai, a Penn chemist. "Our work suggests quite strongly that folding is a far richer phenomenon. Like skiers, some proteins rocket down an energy gradient to their destination while others take their time, meandering indiscriminately."

Though a fleeting phenomenon, the folding of gangly proteins into tight three-dimensional shapes has broad implications for the growing group of human diseases believed to result from misfolded proteins, most notably neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. The characteristic plaques that cripple the brains of Alzheimer’s and Parkinson’s patients are believed to be the dumping grounds for aberrant proteins.

Gai’s work subtly shifts scientists’ understanding of one possible remedy: molecular chaperones, promising compounds that "rescue" misfolded proteins and are believed capable of blocking the progression of neurodegenerative disease. Rather than giving sluggish proteins the oomph to finish folding, the Penn work indicates that chaperones may return misfolded proteins to an unfolded state so they can start all over again.

"In the skiing analogy, chaperones could be thought of as rescue helicopters that return wayward skiers to the summit so they can try to make their way down the mountain again," said Gai, an assistant professor of chemistry at Penn.

Gai’s basic research could lead to drugs that mimic chaperones’ role in fending off neurodegenerative diseases. The work might also yield artificial proteins precisely engineered to fold into biologically active configurations.

Protein folding is fiendishly intricate, yet crucial to the chemistry of life – so much so that a small army of biologists and chemists has devoted itself to better understanding the process. Each of the body’s 20 amino acids, the building blocks of proteins, is habitually attracted or repulsed by water; it’s largely these affinities that drive the as-yet-unpredictable contorting of proteins into three-dimensional shapes within the aqueous environment of a cell.

Gai and his colleagues traced protein folding by zapping samples of 20-amino-acid proteins with a one-nanosecond laser, momentarily heating them enough to unfold the proteins completely. Using infrared spectroscopy, they then observed, nanosecond by nanosecond, how quickly the cohort of proteins refolded into biochemically stable, three-dimensional shapes. It turned out that the time to refold varied tremendously, offering powerful if indirect evidence that the proteins weren’t following a single, prescribed pathway from unfolded to folded after all.

Gai was joined on the PNAS paper by Cheng-Yen Huang, Yongjin Zhu and Jason W. Klemke of Penn’s Department of Chemistry and Zelleka Getahun and William F. DeGrado of the Department of Biochemistry and Biophysics in Penn’s School of Medicine. Their work was supported by Research Corporation, the University of Pennsylvania Research Foundation and the National Science Foundation.


Story Source:

The above story is based on materials provided by University Of Pennsylvania. Note: Materials may be edited for content and length.


Cite This Page:

University Of Pennsylvania. "The Path To A Folded Protein, Long A Subject Of Debate, Appears In Many Cases To Be Long And Winding." ScienceDaily. ScienceDaily, 27 February 2002. <www.sciencedaily.com/releases/2002/02/020227071809.htm>.
University Of Pennsylvania. (2002, February 27). The Path To A Folded Protein, Long A Subject Of Debate, Appears In Many Cases To Be Long And Winding. ScienceDaily. Retrieved July 23, 2014 from www.sciencedaily.com/releases/2002/02/020227071809.htm
University Of Pennsylvania. "The Path To A Folded Protein, Long A Subject Of Debate, Appears In Many Cases To Be Long And Winding." ScienceDaily. www.sciencedaily.com/releases/2002/02/020227071809.htm (accessed July 23, 2014).

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