Cysteine variants in PMM2 lead to protein instability and higher sensitivity to oxidative stress in PMM2-CDG

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• PMM2-congenital disorder of glycosylation (PMM2-CDG) arises from PMM2 gene defects, with limited therapeutic options.
• Cysteine residues are susceptible to oxidative damage, potentially driving disease pathogenesis.
• Five specific cysteine-mutants in PMM2 have been linked to PMM2-CDG, but mechanisms are unclear.

Purpose of the Study:

• To investigate the molecular mechanisms underlying PMM2-CDG caused by cysteine pathogenic mutants.
• To explore the impact of oxidative stress on these PMM2 variants.
• To identify potential therapeutic interventions for PMM2-CDG.

Main Methods:

• Comparison of wild-type (WT) PMM2 with five cysteine pathogenic mutants.
• Assessment of structural integrity, thermal stability, aggregation propensity, and oxidative stress sensitivity.
• Molecular dynamics simulations to analyze core region alterations and subunit binding free energy.
• Literature review for potential therapeutic agents like celastrol.

Main Results:

• Cysteine mutants exhibited structural damage, increased hydrophobic exposure, reduced thermal stability, and aggregation at physiological temperatures.
• Mutants showed heightened sensitivity to oxidative stress, exacerbating aggregation.
• Molecular dynamics simulations indicated altered PMM2 core structure and subunit interactions due to pathogenic variants.
• Celastrol demonstrated potential in partially rescuing cysteine pathogenic mutants.

Conclusions:

• Specific cysteine variants in PMM2 significantly impact enzyme structure and function, contributing to PMM2-CDG.
• Oxidative stress plays a crucial role in the aggregation and pathogenicity of these mutants.
• These findings provide a basis for developing novel therapeutic strategies targeting PMM2-CDG, potentially involving celastrol.