Jianxing Song Pages 294 - 306 ( 13 )
An increasing spectrum of diseases more than neurodegenerative diseases is characteristic of aggregation of specific proteins, while aggregation of a large number of non-specific proteins are associated with aging down to Escherichia coli. Triggered by disease-causing mutations and agingassociated damages, many well-folded cytosolic proteins become “completely insoluble” in vivo. As facilitated by our discovery in 2005 that “completely insoluble” proteins could be solubilized in unsalted water, we have deciphered that disease- and aging-associated factors act to eliminate the native folds of human VAPB-MSP and SOD1, as well as E. coli S1 ribosomal protein, consequently unlocking amphiphilic/hydrophobic regions universally existing in proteins. These disordered states with hydrophobic patches unavoidably exposed are only soluble in unsalted water but become “insoluble” in vivo with high salt concentrations. Most unexpectedly, we decoded that these disordered states acquire novel capacity to interact with membranes energetically driven by forming helices in membrane environments. Remarkably, the abnormal insertion of SOD1 mutants into ER membrane has been functionally established to trigger ER stress, an initial event of a cascade of cell specific damages in ALS pathogenesis. Together with previous results that all aggregation-prone proteins causing diseases contain “intrinsic” membrane-interacting regions, our results with “acquired” membrane- interacting capacity suggest that abnormal interactions with membranes represent a common mechanism for aggregation-prone proteins to trigger diseases and aging. Proteins, the most important functional players for all forms of life, can transform into membrane-toxic forms, if their hydrophobic/ amphiphilic regions are unlocked by genetic, pathological, or/and environmental factors, which is characteristic of aggregation.
Protein aggregation, neurodegenerative diseases, Amyotrophic Lateral Sclerosis (ALS), aging, amphiphilic helix, biological membranes, Major Sperm Protein (MSP) domain, VAPB-3, Superoxide Dismutase 1 (SOD1), Transactivation Response element (TAR) DNA-binding protein 43 (TDP-43), E. coli S1 ribosomal protein, NMR spectroscopy.
Department of Biological Sciences, Faculty of Science, National University of Singapore; 10 Kent Ridge Crescent, 119260