4.6 Article

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

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 26, Pages 10303-10313

Publisher

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.002087

Keywords

amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); protein folding; protein misfolding; aggregation; amyloid; neurodegenerative disease; profilin; ALS; Lou Gehrig Disease; protein dynamics; protein self-assembly

Funding

  1. Italian Ministero dell'Istruzione, dell'Universita e della Ricerca, Progetto di Interesse Invecchiamento
  2. Programma per Giovani Ricercatori Rita Levi Montalcini 2010
  3. Sapienza University of Rome [C26A155S48, B52F16003410005, RP11715C34AEAC9B]

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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 fluorescence, revealing its amyloidogenic potential. Moreover, in the variants tested, we found a correlation between conformational stability of PF and aggregation propensity, defining this conformational state as an aggregation-prone folding intermediate. In conclusion, our findings indicate that mutation-induced stabilization of a partially folded state can enhance profilin-1 aggregation and thereby contribute to the pathogenicity of the mutations.

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