Fleetingly ordered structures from intrinsically disordered protein identified

A team of scientists from The Scripps Research Institute and the University of California, San Diego (UCSD) have developed a novel technique to observe previously unknown details of how folded structures are formed from an intrinsically disordered protein.

The insights could help scientists to better understand the mechanism of plaque formation in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases.
The results of the study, which has broad implications for the field, were recently published in an advanced, online issue of the journal Nature Methods.

The new technique allows previously unheard-of rapid detection-in less than 0.001 seconds-of transiently folded single-molecule structures from a class of often-amorphous molecules known as ''intrinsically disordered proteins.'' The method also permits new types of observations of short-lived protein complexes.

''This exciting new technique allowed us to visualize multiple short-lived folded states,'' said Scripps Research Associate Professor Ashok Deniz, Ph.D., who led the study with UCSD Professor Alex Groisman, Ph.D., and Yann Gambin, Ph.D., of Scripps Research. ''Further, better understanding of complexity during folding may offer more ways to regulate this interesting class of proteins.''

The specific protein examined in the study was a-synuclein, which is highly concentrated in neural tissue. The protein has been implicated in Parkinson's and Alzheimer's diseases, as it is found in high concentrations in aggregates from the brains of patients with these conditions.

Mixing it up
Unlike typical proteins in the cell, intrinsically disordered proteins such as a-synuclein do not adopt a stable globular form in isolation. Rather, intrinsically disordered proteins are like a messy, unfolded string of yarn, whereas typical globular proteins more closely resemble yarn neatly knit into complicated and functional shapes like that of a glove.