• 1 Institute of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London, United Kingdom
  • 2 MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, United Kingdom
  • 3 Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom
PLoS Comput Biol, 2021 03;17(3):e1008708.
PMID: 33651795 DOI: 10.1371/journal.pcbi.1008708


Alternative splicing can expand the diversity of proteomes. Homologous mutually exclusive exons (MXEs) originate from the same ancestral exon and result in polypeptides with similar structural properties but altered sequence. Why would some genes switch homologous exons and what are their biological impact? Here, we analyse the extent of sequence, structural and functional variability in MXEs and report the first large scale, structure-based analysis of the biological impact of MXE events from different genomes. MXE-specific residues tend to map to single domains, are highly enriched in surface exposed residues and cluster at or near protein functional sites. Thus, MXE events are likely to maintain the protein fold, but alter specificity and selectivity of protein function. This comprehensive resource of MXE events and their annotations is available at: These findings highlight how small, but significant changes at critical positions on a protein surface are exploited in evolution to alter function.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.