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Mar 9, 2009

Scientists Describe Molecular Process that Leads to Protein Clumps in Huntington's

  • Researchers at the University of Pittsburgh School of Medicine worked out the details of how the aggregation behavior of huntingtin depends on the neighboring segments of amino acid sequence flanking polyglutamine.

    It is known that while most people have a huntingtin protein whose polyglutamine segment contains 20 to 35 glutamines, patients with Huntington’s have a block of 40 repeats or more. “Polyglutamine doesn't seem to play a sophisticated role in these proteins, and it doesn't have a defined structure,” points out Ronald Wetzel, Ph.D., professor in the department of structural biology. “Yet by changing its length to only a very slight extent, it takes on some new physical properties that somehow initiate diseases.”

    The Pitt team found that longer polyglutamine sequences have the ability to disrupt the structure of a neighboring region, 17 amino acids long, at the beginning of the protein known as the N-terminus. That sets the stage for new physical interactions with the rest of the huntingtin protein that drive it to aggregate.

    “If the N-terminus is not there, huntingtin makes clumps very slowly, even if the polyglutamine stretch is rather long,” Dr. Wetzel notes. “When the N-terminus is disrupted by its polyglutamine neighbor, it takes a lead role in the aggregation process, with the polyglutamine then following to consolidate and stabilize the clumps in a kind of aggregation two-step.”

    These results appear in the early online version of Nature Structural and Molecular Biology.



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