Effect of Mutation on an Aggregation-Prone Segment of p53: From Monomer to Dimer to Multimer

Area of Science:

• Biophysics
• Molecular Biology
• Cancer Research

Background:

• Protein aggregation and amyloid formation are linked to various diseases.
• Amyloid formation of tumor suppressor p53 can impair its function, potentially accelerating cancer progression.
• Understanding p53 aggregation mechanisms is crucial for designing effective cancer therapeutics.

Purpose of the Study:

• To characterize the aggregation process of an aggregation-prone p53 fragment (residues 252-258).
• To evaluate the efficacy of the I254R mutant in suppressing p53 aggregation.
• To elucidate the structural and mechanical changes induced by the I254R mutation.

Main Methods:

• Atomistic simulations were employed to study p53 fragment aggregation.
• The study analyzed the structural stability and mechanical dissociation of wild-type and mutant p53 fragments.
• Aggregation propensity and self-assembly characteristics were investigated.

Main Results:

• The wild-type p53 fragment forms stable, parallel β-sheet rich dimers that dissociate sequentially under force.
• The wild-type fragment exhibits high aggregation propensity, forming parallel peptide structures.
• The I254R mutation destabilizes the dimer, alters dissociation to cooperative unfolding, reduces aggregation propensity, and changes peptide orientation in aggregates.
• Adding the wild-type sequence partially restores the aggregation propensity of the I254R mutant.

Conclusions:

• The I254R mutation significantly impacts p53 fragment aggregation, reducing its propensity and altering its structural dynamics.
• These findings provide insights into the molecular mechanisms of p53 aggregation and potential therapeutic strategies.
• Further research can explore the modulation of p53 aggregation for cancer treatment.