Structural genomics analysis of alternative splicing and application to isoform structure modeling

Area of Science:

• Molecular Biology
• Structural Biology
• Bioinformatics

Background:

• Alternative splicing regulates gene expression and protein functional diversity.
• Knowledge gaps exist regarding the protein tertiary structures of alternatively spliced variants, primarily studied via mRNA.
• Understanding these structures is crucial for comprehending protein function.

Purpose of the Study:

• To analyze alternatively spliced variants at both sequence and structure levels.
• To assess the viability of protein structure modeling for these variants.
• To establish a genome-scale method for predicting structures of alternatively spliced isoforms.

Main Methods:

• Large-scale analysis of known alternatively spliced variants.
• Protein structure modeling using the threading approach.
• Examination of splicing event characteristics at sequence and structural levels.
• Molecular dynamics simulations to assess fold stability.

Main Results:

• Threading is a generally viable approach for modeling alternatively spliced variant structures.
• Splicing event sizes follow a power law distribution; most isoforms have few alternations.
• Alternative splicing boundaries occur in coil regions and on exposed residues, primarily on protein surfaces.
• Threading-based structure prediction is feasible and fold stability can be addressed.

Conclusions:

• A viable method for predicting alternatively spliced isoform structures at the genome scale has been established.
• Threading is a useful tool for structure prediction of alternatively spliced isoforms.
• Insights into splicing event locations inform structure prediction strategies.