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New probes from Scripps research quantify folded and misfolded protein levels in cells

LA JOLLA, CA March 4, 2014 Scientists at The Scripps Research Institute (TSRI) have invented small-molecule folding probes that enable them to quantify functional, normally folded and disease-associated misfolded conformations (shapes) of a protein-of-interest in cells under different conditions.

Scientists have long needed better tools for making such measurements in cells, because protein misfolding is a major cause of damage to tissues. Disorders that feature excessive protein misfolding afflict millions of people worldwide and include Alzheimer's and Parkinson's diseases, the systemic amyloidoses and prion ("mad cow-type") infections, as well as common enzyme deficiencies.

"This new probe technology should lead to a better understanding of how to fold misfolding-prone proteins in cells," said Jeffery W. Kelly, chair of TSRI's Department of Molecular and Experimental Medicine, Lita Annenberg Hazen Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI.

"The ability to quantify protein folding in a cell using this simple fluorescence-based technology should speed the development of new therapies."

The study, led by Kelly and his laboratory, is reported in this week's online Early Edition of the Proceedings of the National Academy of Sciences.

Profound Consequences

Misfolded proteins have never been easy to distinguish from their normally folded counterparts, especially within cells, because both have the same sequence of amino acids. Yet the loss of the normally folded shape can have profound consequencesa misfolded protein typically will lose its function within a cell. Worse, misfolding may expose "sticky," previously concealed parts of a protein that cause it to start aggregating with other copies of itself, leading to dysfunction of tissue that does not easily regenerate.

Both loss-of-function and gain-of-toxic function mutations can lead to dise

Contact: Mika Ono
Scripps Research Institute

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