Light up Dark Side of Proteins with Pure Water For NMR Visualization
Jianxing Song · 2015
Aggregation of specific proteins has been emerging as causes of an increasing spectrum of human diseases including all neurodegenerative diseases, while aggregation of non-specific proteins has been recently identified to be the marker of aging down to unicellular organisms. The gain of cellular toxicity is thus expected to be a common mechanism for aggregation-prone proteins to initiate diverse diseases as well as aging. However, many such proteins are “completely insoluble” and therefore could not be studied previously by high-resolution biophysical methods including NMR spectroscopy. Nevertheless, in 2005, we discovered that insoluble proteins could be in fact solubilized in unsalted water and this makes NMR as the only tool for studying atomic resolution conformations of “insoluble proteins”. Recently, we have been focused on NMR characterization of insoluble proteins/mutants causing amyotrophic lateral sclerosis (ALS) including P56S-MSP, SOD1 and TDP-43. Our results deciphered that strikingly ALS-causing mutations act to eliminate their native structures, thus rending the mutants into highly-disordered states which become extremely insoluble in vivo or in buffers. Surprisingly, the aggregation of the TDP-43 N-terminus is attributed to the coexistence of folded and unfolded states exchangeable at 14 Hz. Most unexpectedly, we decoded that these aggregation-prone proteins can transform into membrane-interacting proteins to manifest their cellular toxicity probably by: 1) disrupting membrane structures and dynamics; or/and 2) perturbing membrane-anchored signal pathways or machinery; or/and 3) interfering in the membrane remodeling. With our results added in, a general conclusion can now be reached that aggregation-prone proteins share a common potential to manifest their toxicity by attacking membranes and membrane-associated processes.