Unlocked capacity of proteins to attack membranes characteristic of aggregation: the evil for diseases and aging from Pandora’s box

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC=\"FIGDIR/small/071274_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (61K):\norg.highwire.dtl.DTLVardef@3e897borg.highwire.dtl.DTLVardef@1b429f6org.highwire.dtl.DTLVardef@12f0dbeorg.highwire.dtl.DTLVardef@2f5d8f_HPS_FORMAT_FIGEXP M_FIG C_FIG AbstractAggregation of specific proteins is characteristic of a large spectrum of human diseases including all neurodegenerative diseases, while aggregation of non-specific proteins has been now identified to be a biomarker for cellular aging down to Escherichia coli. Previously, as facilitated with our discovery in 2005 that \"completely insoluble\" proteins could be all solubilized in unsalted water [Song (2009) FEBS Lett. 583: 953], we found that the TDP-43 prion-like domain in fact contains an intrinsic membrane-interacting subdomain [Lim et al. [2016] PLoS Biol. 14, e1002338]. We decrypted that ALS-causing mutations/cofactor-depletion act to render the wellstructured folds of cytosolic VAPB-MSP domain and SOD1 into highly disordered states, thus becoming buffer-insoluble. Most surprisingly, this also unlocks the amphiphilic/hydrophobic regions universally exiting in proteins, which thus acquire a novel capacity in abnormally interacting with membranes [Qin et al. (2013) F1000Res 2-221.v2; Lim (2016) BBA-Biomembranes. 1858: 2223]. Here we aimed extend our discovery to address two fundamental questions: 1) why many E. coli proteins become aggregated in aging; and 2) whether aggregation-prone proteins can also acquire a novel capacity in interacting with membranes; by dissecting the 557-residue S1 ribosomal protein into 7 fragments to disrupt its 6 S1 folds, followed by extensive CD and NMR characterizations. The results reveal that we have successfully eliminated all 6 S1 folds and fragment 4 becomes highly disordered and thus buffer-insoluble. Most strikingly, F4 does acquire a capacity in transforming into a helical conformation in membrane environments. Here, for the first time, our study deciphers that like ALScausing mutants, the disruption of a well-folded E. coli cytosolic protein also unlocks its amphiphilic/hydrophobic regions which are capable of abnormally interacting with membranes. Therefore, proteins, the most important functional players for all forms of life, can transform into membrane-toxic forms triggering diseases and aging, if their hydrophobic/amphiphilic regions are unlocked by genetic, pathological or/and environmental factors, which is characteristic of severe aggregation.