It seems that lately you can't pick up a paper or turn on the TV without being confronted with reports of mad cow disease and its human equivalent, variant Creutzfeld-Jacob disease (vCJD). These diseases have something in common with other disorders, including Alzheimer's disease -- protein plaques get deposited into the brain where they presumably destroy tissue.
These plaques are composed of fibrils of certain proteins, prion proteins in the case of mad cow disease and vCJD and amyloid beta proteins in the case of Alzheimer's disease. Although it has not been rigorously proven that the protein plaques are the direct cause of the nerve degeneration seen in affected cattle and people, it seems a highly probable scenario.
How these fibrils of proteins form from many identical molecules of a single type of protein is not well understood. Clearly, the individual protein molecules must interact in some regular and stable way to form the linear fibrils that eventually group together to form a plaque. For some time, researchers have suggested that a particular type of interaction, known as 'domain swapping' may be involved in fibril formation, and now two recent studies published in Nature Structural Biology support this idea.
'Domain swapping' means that two proteins of identical structure may swap the same structural element -- say, one alpha-helix or one beta-strand -- to complete each other's final fold. The result is a pair of linked proteins with identical structures, instead of two unlinked proteins with the same structure. A way to visualize this might be to imagine two people shaking hands: separately they each have all the same parts in basically the same shape, but when they link hands -- the identical structural elements -- they 'swap' parts to become a linked pair.
In the April issue of Nature Structural Biology (Vol. 8, No. 4, 01 Apr 2001), Mariusz Jaskolski, of the Center for Biocrystallographic Research in Poland, and colleagues have solved the structure of human cystatin C, another protein that can form deposits in the brain, in this case leading to fatal cerebral hemorrhage. They show that this protein can form 'domain swapped' pairs of proteins.
In the March issue of Nature Structural Biology, David Eisenberg, of UCLA in the USA, and colleagues showed that another protein, called RNase A, can actually form two different types of 'domain swapped' protein pairs. In the two different cases, different structural elements are swapped. This suggests a way that a fibril of linked proteins could be generated. Using the hand-shaking analogy described above, if the two different structural elements are the two hands of an individual, then a linked chain of people could form by linking hands -- by swapping the different structural elements in regular order, to build a chain of molecules.
Although the RNase A protein is not known to form plaques in the body, if a similar 'double domain swapping' mechanism could be used by plaque-forming proteins such as human cystatin C, prions, and amyloid-beta, then this might explain how the stable plaque-forming fibrils grow.
Marcia Newcomer discusses these two papers in a News and Views report, and the Editorial discusses mad cow disease and vCJD.
Dr. Mariusz Jaskolski
Polish Academy of Sciences
Department of Crystallographgy
A. Mickiewicz University
Telephone: +48 48 61 829 1274
Fax: +48 61 865 8008
Dr. David Eisenberg
University of California-Los Angeles
Molecular Biology Institute
Dept. of Chemistry & Biochemistry
405 Hilgard Avenue
Los Angeles, CA 90095
Telephone: +1 310 825 3754
Fax: +1 310 206 3914/7286
Dr. Marcia E. Newcomer
Vanderbilt University School of Medicine
Dept of Biochemistry
Room 868 MRB
Nashville, TN 37232-0146
Telephone: +1 615 343 7333
Fax: +1 615 343 1898
(C) Nature Structural Biology press release.
Message posted by: Trevor M. D'Souza
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