Simulation and Computational Study of RING Domain Mutants of BRCA1 and Ube2k in AD/PD Pathophysiology

Area of Science:

• Biochemistry and Molecular Biology
• Neuroscience
• Genetics

Background:

• Lysine-based post-translational modifications (PTMs), including ubiquitination, are crucial regulators of cellular processes.
• Ubiquitination, mediated by the ubiquitin-proteasome system (UPS), is vital for protein degradation and implicated in neurodegenerative diseases (NDDs) like Alzheimer's (AD) and Parkinson's (PD).
• Impaired UPS function, particularly E3 ligase dysfunction, accelerates neurodegeneration.

Purpose of the Study:

• To identify common E3 ligases in both AD and PD through data mining.
• To investigate the structural and functional impact of mutations in identified E3 ligases.

Main Methods:

• Data mining to identify common E3 ligases in AD and PD.
• Protein-protein interaction, pathway enrichment, lysine site prediction, domain, and motif analysis.
• Structural characterization and molecular dynamics simulation of BRCA1 mutations.

Main Results:

• Identified 74 common E3 ligases between AD and PD, with BRCA1, PML, and TRIM33 highlighted as top candidates.
• BRCA1's RING domain mutations (K32Y, K32L, K32C, K45V, K45Y, K45G) were predicted to alter its structure and function.
• Molecular dynamics simulation identified K32L as the most probable mutant, significantly affecting BRCA1's interaction with Ube2k.

Conclusions:

• BRCA1 is a potential E3 ligase common to both AD and PD pathogenesis.
• Mutations in BRCA1's RING domain, specifically at K32 and K45, likely impair its interaction with the E2-conjugating enzyme Ube2k.
• These disruptions may contribute to the progression of neurodegenerative diseases.