Selective constraint on human pre-mRNA splicing by protein structural properties.

Area of Science:

• Molecular Biology
• Genomics
• Structural Biology

Background:

• Alternative splicing (AS) significantly increases proteome diversity by generating various transcript isoforms.
• These isoforms can lead to peptides with different lengths and amino acid compositions, raising questions about structural constraints.

Purpose of the Study:

• To investigate whether protein structural requirements, specifically the intactness of protein units (PUs), influence alternative splicing events in humans.
• To determine if PUs constrain AS by preserving structural integrity during exon skipping or inclusion.

Main Methods:

• Analysis of human mRNA sequences and their corresponding protein structures.
• Identification and localization of protein units (PUs) within exons and at exon boundaries.
• Comparison of splicing patterns of exons overlapping with PUs versus those that do not.

Main Results:

• Protein units (PUs) are preferentially found in constitutively spliced exons and overlap constitutive exon boundaries.
• Alternatively spliced exons (ASEs) bordering PUs tend to co-occur in transcript isoforms and are more frequently included.
• ASE regions overlapping PUs exhibit lower nonsynonymous-to-synonymous substitution rates, indicating stronger negative selection.
• The influence of PUs on splicing is independent of protein domains and structural orderness.

Conclusions:

• Fine-scale protein structural requirements significantly impact alternative splicing patterns in human mRNAs.
• The preservation of protein unit (PU) intactness acts as a constraint on alternative splicing, favoring specific isoform combinations.