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Mechanism Of Protein Folding Unraveled, With Eventual Implications For Treating Diseases Caused By Folding Errors

Date:
October 5, 1998
Source:
University Of Pennsylvania Medical Center
Summary:
The process of how a protein changes from an initially shapeless string of amino acids to a three-dimensional structure with nooks and crannies of biologically active sites is often called the second half of the genetic code. This transformation is called protein folding. Research at the University of Pennsylvania Medical Center has recently added some revealing clues as to how this conversion is managed and corrects some misconceptions about how rapidly folding occurs.

The process of how a protein changes from an initially shapeless string of amino acids to a three-dimensional structure with nooks and crannies of biologically active sites is often called the second half of the genetic code. This transformation is called protein folding.

Research at the University of Pennsylvania Medical Center has recently added some revealing clues as to how this conversion is managed and corrects some misconceptions about how rapidly folding occurs. This active area of research has taken on even more importance with the growing knowledge that errors in protein folding can lead to such deadly and debilitating disorders as Alzheimer's disease, Huntington's-related diseases, and prion-related encephalopathies. A report on this study appears in today's issue of Nature Structural Biology.

How a protein manages to fold is a seemingly impossible problem, suggests S. Walter Englander, PhD, a professor of biochemistry and biophysics at the University of Pennsylvania School of Medicine: "Even with a small, 100-amino-acid-long protein, the number of possible three-dimensional structures that the protein might manifest is larger than the number of molecules in the universe." Protein biologists believe that the amino-acid sequences laid out by the genetic machinery contain chemical instructions for the pathway that carries each protein to its final structure.

The Penn experiments show that the amino-acid chain progresses through a series of pre-determined, intermediate arrangements. Englander's lab has demonstrated that the protein cytochrome c builds its structure in steps by first making helices at either end that lay at right angles to each other. Then, strands, loops, and other helices build up against that initial foundation until the final arrangement is reached. All this can occur in less than one second, but trouble can arise along the way. "A few years ago we showed that on the complicated journey to their final structure, proteins have a large tendency to make mistakes that greatly slow them down," notes Englander. "Proteins need to fold fast because if they spend too much time in one intermediate state, they're vulnerable to aggregation with other proteins in the midst of folding, which can be very destructive to the cell."

The recent work straightens out misinterpretations about how fast this process can proceed. "Numerous papers published in the past two years all conclude that when you initiate folding in a rapid reaction experiment, you see some very fast sub-millisecond optical signal changes, as well as some slower ones" explains Englander. "This has always been interpreted as a rapid formation of some real structural intermediates. It is crucially important to understand which of these signals represent real protein behavior and which give you misleading clues that simply depend on the kind of experiment you are doing. Understanding the folding process and the real time scale of events begins to give you some idea of what you can do to fight diseases like Alzheimer's."

Englander's lab performed experiments that convincingly showed that these exceedingly fast initial signals are not real intermediates, but simply represent the protein stretching and pulling in the denaturing solution used in the experiment. The researchers made two copies of the same amino-acid chain, one that couldn't fold and one that could, and observed that both versions displayed the same initial ultra-fast burst of optical activity.

This work was conducted in the Johnson Research Foundation, a funding and research organization within Penn's Department of Biochemistry and Biophysics that concentrates on the study of physics as it applies to medicine.


Story Source:

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


Cite This Page:

University Of Pennsylvania Medical Center. "Mechanism Of Protein Folding Unraveled, With Eventual Implications For Treating Diseases Caused By Folding Errors." ScienceDaily. ScienceDaily, 5 October 1998. <www.sciencedaily.com/releases/1998/10/981005074228.htm>.
University Of Pennsylvania Medical Center. (1998, October 5). Mechanism Of Protein Folding Unraveled, With Eventual Implications For Treating Diseases Caused By Folding Errors. ScienceDaily. Retrieved August 20, 2014 from www.sciencedaily.com/releases/1998/10/981005074228.htm
University Of Pennsylvania Medical Center. "Mechanism Of Protein Folding Unraveled, With Eventual Implications For Treating Diseases Caused By Folding Errors." ScienceDaily. www.sciencedaily.com/releases/1998/10/981005074228.htm (accessed August 20, 2014).

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