Resolving the paradox for protein aggregation diseases: a common mechanism for aggregated proteins to initially attack membranes without needing aggregates

Abstract

Paradoxically, aggregation of specific proteins is characteristic of many human diseases and aging, yet aggregates have been found to be unnecessary for initiating pathogenesis. Here we determined the NMR topology and dynamics of a helical mutant in a membrane environment transformed from the 125-residue cytosolic all-β MSP by the ALS-causing P56S mutation. Unexpectedly, despite its low hydrophobicity, the P56S major sperm protein (MSP) domain becomes largely embedded in the membrane environment with high backbone rigidity. Furthermore it is composed of five helices with amphiphilicity comparable to those of the partly-soluble membrane toxin mellitin and α-synuclein causing Parkinson's disease. Consequently, the mechanism underlying this chameleon transformation becomes clear: by disrupting the specific tertiary interaction network stabilizing the native all-β MSP fold to release previously-locked amphiphilic segments, the P56S mutation acts to convert the classic MSP fold into a membrane-active protein that is fundamentally indistinguishable from mellitin and α-synuclein which are disordered in aqueous solution but spontaneously partition into membrane interfaces driven by hydrogen-bond energetics gained from forming α-helix in the membrane environments. As segments with high amphiphilicity exist in all proteins, our study successfully resolves the paradox by deciphering that the proteins with a higher tendency to aggregate have a stronger potential to partition into membranes through the same mechanism as α-synuclein to initially attack membranes to trigger pathogenesis without needing aggregates. This might represent the common first step for various kinds of aggregated proteins to trigger familiar, sporadic and aging diseases. Therefore the homeostasis of aggregated proteins is the central factor responsible for in vivo a variety of human diseases including aging. The number and degree of the membrane attacks by aggregated proteins may act as an endogenous clock to count down the aging process. Consequently, a key approach to fight against them is to develop strategies and agents to maintain or even enhance the functions of the degradation machineries.

Mechanistic Insights into Protein Stability and Self-aggregation in GLUT1 Genetic Variants Causing GLUT1-Deficiency Syndrome

“…Yet, qualitatively similar shapes of aggregation free energy profiles suggest that WT and GLUT1 mutants exist in thermodynamically unfavorable conformation. This agrees well with the notion that proteins containing intrinsically disordered regions, including the WT proteins, are prone to misfolding (Qin et al 2013). However, mutations further promote the aggregation of the protein.…”

“…Lastly, GLUT1 mutants with a higher propensity to aggregate might exhibit stronger potential to partition into membranes and cause pathogenesis. The homeostasis of aggregated proteins may trigger sporadic and familial disease (Qin et al 2013), similar to what has been described for many aggregated proteins in diseased states.…”

“…It is also possible that TM9, which is included in predicted aggregation-prone regions, could determine an initial aggregation of GLUT1 tetramers. However, genetic mutations might increase the aggregation potential by triggering redundant interactions, further destabilizing GLUT1 conformation (Qin et al 2013).…”