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Aip1p Dynamics Are Altered by the R256H Mutation in Actin
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A Disease-Associated Mutation Impedes PPIA through Allosteric Dynamics Modulation.

Yoshikazu Hattori1, Munehiro Kumashiro1, Hiroyuki Kumeta2

  • 1Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.

Biochemistry
|June 30, 2025
PubMed
Summary
This summary is machine-generated.

A K76E mutation in Peptidylprolyl cis-trans isomerase A (PPIA) impairs its function in Amyotrophic Lateral Sclerosis (ALS) by disrupting protein dynamics, not structure. This finding offers new insights into ALS molecular mechanisms.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Amyotrophic Lateral Sclerosis (ALS) involves motor neuron degeneration.
  • Peptidylprolyl cis-trans isomerase A (PPIA) is a molecular chaperone implicated in ALS pathogenesis.
  • A K76E mutation in PPIA has been identified in sporadic ALS patients.

Purpose of the Study:

  • To investigate the structural and functional consequences of the K76E mutation in PPIA.
  • To understand the molecular mechanisms of PPIA dysfunction in ALS.

Main Methods:

  • Biochemical and biophysical techniques were employed.
  • Relaxation dispersion NMR experiments were utilized.
  • Theoretical kinetic analysis was performed.

Main Results:

  • The K76E mutation significantly reduced PPIA enzyme activity.
  • Protein structure, monodispersity, and substrate recognition remained unaffected.
  • NMR data revealed disrupted protein dynamics and an altered allosteric network in the K76E mutant.

Conclusions:

  • The K76E mutation impairs PPIA function primarily by disrupting protein dynamics, not direct structural changes.
  • Altered dynamics slow the cis-trans isomerase activity of the K76E mutant.
  • This study provides insights into ALS-associated mutations and their impact on protein function.