T253X Mutations Alter Local Structure and Trigger Tyr236 Hydration in p53 DNA-Binding Domain

Area of Science:

• Molecular biology
• Structural biology
• Cancer research

Background:

• Mutations in the p53 tumor suppressor's DNA-binding domain (DBD) are frequent in cancers.
• Threonine 253 (Thr253) is in an aggregation-prone region, and its substitutions are linked to inherited cancer predisposition.
• The structural impact of Thr253 mutations is not well understood.

Purpose of the Study:

• To investigate the conformational dynamics of wild-type (WT) p53 DBD and four Thr253 variants.
• To elucidate the structural consequences of Thr253 mutations on p53 stability and DNA binding.
• To understand the role of the Tyr236-Thr253 interaction in p53 DBD stability.

Main Methods:

• All-atom molecular dynamics simulations were performed on WT p53 DBD and four T253 variants (T253A, T253P, T253I, T253N).
• Analysis focused on conformational changes, stability elements, and hydrogen bonding patterns.
• The study examined the local response of the Tyr236 residue and surrounding loops to Thr253 substitutions.

Main Results:

• T253 mutations remodel a local stability element involving Tyr236, Thr253, and adjacent loops.
• All T253 variants disrupt the Tyr236-Thr253 hydrogen bond in the hydrophobic core.
• This disruption causes Tyr236 to interact with water molecules, altering local hydration and stability.

Conclusions:

• The Tyr236-Thr253 region is a stability hotspot in the p53 DBD.
• Mutations at Thr253 subtly alter buried interactions and hydration, impacting function.
• These findings provide a mechanistic basis for understanding p53 variants in cancer predisposition.