Comprehensive in silico analyses of keratin heterodimerisation

Area of Science:

• Biochemistry and Structural Biology
• Cell Biology
• Computational Biology

Background:

• Keratins are essential intermediate filament proteins providing epithelial cell structural integrity.
• The molecular basis and specific pairing preferences of keratin heterodimerization are not well understood.

Purpose of the Study:

• To systematically investigate keratin heterodimerization using a computational pipeline.
• To establish a guideline for analyzing intermediate filament assembly.
• To uncover the structural principles underlying keratin dimer formation.

Main Methods:

• Integrated high-throughput computational pipeline including AlphaFold Multimer (AFM) modeling.
• VoroIF-GNN interaction interface quality assessment and interaction energy calculations.
• Structural comparisons with experimental data and spatial transcriptomics analysis.

Main Results:

• Keratin heterodimers exhibit lower interaction energies and favorable configurations compared to homodimers.
• The coil 1 region is identified as crucial for keratin dimer stability.
• Computational predictions show strong agreement with experimental data for vimentin homodimers.
• Co-expression patterns of keratin pairs are observed in skin tissue data.

Conclusions:

• Established a robust computational workflow for studying keratin heterodimerization.
• Highlighted fundamental structural principles governing keratin dimer assembly.
• Provided insights into keratin function in physiological and pathological conditions.