[Currents header graphic]

April 14, 1997

Partially folded proteins yield clues about how they aggregate and cause disease

Proteins are the cell's dependable workhorses. Sometimes, though, they behave like old wire hangars in the back of your closet, snarling into useless tangles. Such aggregates can trigger debilitating diseases, such as Alzheimer's and primary amyloidosis. Now, UCSC chemists are helping to unravel how those microscopic messes arise.

Newly born proteins emerge from their cellular factories as long strings of amino acids, which can take up to a minute to fold into their proper shapes. However, it seems that neither the unfolded strings nor the fully folded proteins are the precursors to protein clumps. Rather, specific stages in the middle of the folding process appear most susceptible to entangling with their neighbors.

Scientists in UCSC biochemist Anthony Fink's lab used detailed spectroscopic techniques to probe troublesome protein knots, known as "inclusion bodies," in living cells. Their structures, the team found, looked much like those of certain aggregates created in laboratory vials. They also resembled other harmful clumps of misfolded proteins called "amyloid deposits."

All of these protein agglomerations were rich in "beta sheets," sets of amino acids that link up in flat, broad patterns. Beta sheets are common in many normal, fully folded proteins; indeed, they often are vital to preserving a protein's overall shape. But if too many of them form in some intermediate stage of the protein-folding process, the proteins may become too sticky--almost as if the beta sheets act like swaths of Velcro.

"For a given protein, it seems that one partially folded intermediate is particularly prone to aggregate," Fink said. "The contacts between the molecules that lead to this aggregation appear to involve increased beta-sheet interactions."

Fink's group hopes to develop a clearer picture of why the clumps form and which cellular conditions seem to favor their growth. With that knowledge, researchers might design ways to prevent or reverse the entanglements. For instance, an engineered protein fragment that complements part of a beta-sheet assembly could inhibit anything else from binding to it--like sealing off the sticky hooks of Velcro with a strip of felt.

Fink will chair a 1997 FASEB Summer Research Conference at which chemists will discuss progress on many of these issues. The conference, "Amyloid and Other Abnormal Protein Assembly Processes," is scheduled for July 13-18 in Copper Mountain, Colorado.

Former graduate student Sangita Seshadri, now at Inhale Therapeutics in Palo Alto, conducted most of the research reported at the ACS meeting. Other contributors were current graduate student Anupam Talapatra and former graduate student Keith Oberg.


Return to list of related articles

Return to the Currents home page