Stability of an aggregation-prone partially folded state of human profilin-1 correlates with aggregation propensity

The Journal of Biological Chemistry
Edoardo Del PoggettoFrancesco Bemporad

Abstract

A set of missense mutations in the gene encoding profilin-1 has been linked to the onset of familial forms of ALS (fALS), also known as Lou Gehrig's disease. The pathogenic potential of these mutations is linked to the formation of intracellular inclusions of the mutant proteins and correlates with the mutation-induced destabilization of its native, fully folded state. However, the mechanism by which these mutations promote misfolding and self-assembly is yet unclear. Here, using temperature-jump and stopped-flow kinetic measurements, we show that, during refolding, WT profilin-1 transiently populates a partially folded (PF) state endowed with hydrophobic clusters exposed to the solvent and with no detectable secondary structure. We observed that this conformational state is marginally stable at neutral pH but becomes significantly populated at mildly acidic pH. Interestingly, the fALS-associated mutations did not cause a change in the refolding mechanism of profilin-1, but induced a stabilization of the PF state. In the presence of preformed profilin-1 aggregates, the PF state, unlike the unfolded and folded states, could interact with these aggregates via nonspecific hydrophobic interactions and also increase thioflavin-T flu...Continue Reading

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Citations

Sep 3, 2020·International Journal of Molecular Sciences·Mirella Vivoli-VegaFrancesco Bemporad
Jun 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Eric J SchmidtDaryl A Bosco
Aug 31, 2021·Frontiers in Cell and Developmental Biology·Kai MurkJuliane Schiweck

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