Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms
Abstract
Alternative splicing of pre-mRNA generates two or more protein isoforms from a single gene, thereby contributing to protein diversity. Despite intensive efforts, an understanding of the protein structure–function implications of alternative splicing is still lacking. Intrinsic disorder, which is a lack of equilibrium 3D structure under physiological conditions, may provide this understanding. Intrinsic disorder is a common phenomenon, particularly in multicellular eukaryotes, and is responsible for important protein functions including regulation and signaling. We hypothesize that polypeptide segments affected by alternative splicing are most often intrinsically disordered such that alternative splicing enables functional and regulatory diversity while avoiding structural complications. We analyzed a set of 46 differentially spliced genes encoding experimentally characterized human proteins containing both structured and intrinsically disordered amino acid segments. We show that 81% of 75 alternatively spliced fragments in these proteins were associated with fully (57%) or partially (24%) disordered protein regions. Regions affected by alternative splicing were significantly biased toward encoding disordered residues, with a vanishingly small P value. A larger data set composed of 558 SwissProt proteins with known isoforms produced by 1,266 alternatively spliced fragments was characterized by applying the pondr vsl1 disorder predictor. Results from prediction data are consistent with those obtained from experimental data, further supporting the proposed hypothesis. Associating alternative splicing with protein disorder enables the time- and tissue-specific modulation of protein function needed for cell differentiation and the evolution of multicellular organisms.
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Cell- and tissue-differentially regulated alternative splicing events are under-represented in folded protein domains and enriched in disordered, surface-accessible regions that embed short linear interaction motifs.
“While cell and tissue differentially-regulated AS events are significantly under-represented in functionally defined, folded domains in proteins, they are enriched in regions of protein disorder that typically are surface accessible and embed short linear interaction motifs (Buljan et al., 2012; Ellis et al., 2012; Romero et al., 2006).”
From A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains (2014) · cites this paper as Romero et al., 2006
The mRNA involved in alternative splicing shows a strong preference to code for disorder rather than for structure (with structured-domain-encoding exon skipping being the main exception).
“The mRNA involved in alternative splicing shows a strong preference to code for disorder rather than for structure (with structured-domain-encoding exon skipping being the main exception to this preference); adding and deleting protein segments is much less disruptive in IDRs than in structured regions [40].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [40]
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- Authors
- Romero, P. R., Zaidi, S., Fang, Y. Y., Uversky, V. N., Radivojac, P., Oldfield, C. J., Cortese, M. S., Sickmeier, M., LeGall, T., Obradovic, Z., & Dunker, A. K.
- Affiliations
- Indiana University Indianapolis (US)
- Indiana University – Purdue University Indianapolis (US)
- School of Informatics, Indiana University, Eigenmann Hall 1005, 1900 East 10th Street, Bloomington, IN 47406; and
- Center for Information Science and Technology, Temple University, 303 Wachman Hall (038-24), 1805 North Broad Street, Philadelphia, PA 19122
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-05-30
- Volume
- 103
- Issue
- 22
- Pages
- 8390-8395
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2119986079
- Cited by
- 480
- References
- 49
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 10 · 2023: 18 · 2022: 23 · 2021: 15 · 2020: 22 · 2019: 22 · 2018: 26 · 2017: 21 · 2016: 27 · 2015: 23 · 2014: 33 · 2013: 37 · 2012: 31
- FWCI
- 13.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons - University of South Florida (University of South Florida) (submittedVersion)
- Funders
- Eli Lilly and Company
- Lilly Endowment
- National Institutes of Health
- U.S. National Library of Medicine (R01LM007688)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- alternative splicing, intrinsically disordered proteins, protein isoforms, protein structure-function relationship, differentially spliced genes, disorder prediction, multicellular organisms, cell differentiation
- MeSH terms
- Animals, Humans, Models, Molecular, Protein Conformation, Proteins, Transcription, Genetic, Alternative Splicing, Protein Isoforms
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