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ALS-causing profilin-1-mutant forms a non-native helical structure in membrane environments.

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Summary

Mutations in profilin 1 (PFN1) cause amyotrophic lateral sclerosis (ALS) similarly to SOD1 mutations. The C71G-PFN1 mutation destabilizes the protein, causing it to interact abnormally with cell membranes, potentially initiating ALS.

Keywords:
ALS-causing C71G mutationAggregationAmyotrophic lateral sclerosis (ALS)Membrane-interacting proteinNMR spectroscopyProfilin 1 (PFN1)

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Structural Biology

Background:

  • Profilin 1 (PFN1) mutations cause amyotrophic lateral sclerosis (ALS), similar to superoxide dismutase 1 (SOD1) mutations, despite different physiological roles.
  • The C71G-PFN1 mutation induces ALS through toxic gain-of-function and accelerated motor neuron degeneration, preceding aggregate formation.

Purpose of the Study:

  • To elucidate the structural and dynamic changes in wild-type (WT) and C71G-PFN1 upon mutation.
  • To investigate the interaction of WT-PFN1 and C71G-PFN1 with membrane mimetics.
  • To understand the molecular mechanism by which C71G-PFN1 contributes to ALS pathogenesis.

Main Methods:

  • Atomic-resolution Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the conformations and dynamics of WT-PFN1 and C71G-PFN1.
  • Experiments were conducted in aqueous buffers and in the presence of membrane mimetics (DMPC/DHPC bicelle and DPC micelle).

Main Results:

  • The C71G mutation thermodynamically destabilizes PFN1, leading to a coexistence with an unfolded state lacking stable structures and restricted backbone motions, similar to ALS-causing SOD1 mutants.
  • While WT-PFN1 shows weak interaction with membrane mimetics, C71G-PFN1 exhibits strong binding, driven by the transformation of the disordered unfolded state into a non-native helical structure.
  • This abnormal membrane interaction of C71G-PFN1 mirrors observations made for ALS-causing SOD1 mutants.

Conclusions:

  • The C71G mutation transforms PFN1 into a state that is structurally and dynamically similar to ALS-associated SOD1 mutants.
  • C71G-PFN1 gains an abnormal capacity to interact strongly with membranes, unlike WT-PFN1.
  • Abnormal membrane interaction is a potential mechanism by which C71G-PFN1 initiates ALS, aligning with recent findings for SOD1 mutants.