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The function of alternative splicing in the proteome: rewiring protein interactomes to put old functions into new contexts

Nature Structural & Molecular Biology volume 30, pages 1844–1856 (2023)Cite this article

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Abstract

Alternative splicing affects more than 95% of multi-exon genes in the human genome. These changes affect the proteome in a myriad of ways. Here, we review our understanding of the breadth of these changes from their effect on protein structure to their influence on interactions. These changes encompass effects on nucleic acid binding in the nucleus to protein–carbohydrate interactions in the extracellular milieu, altering interactions involving all major classes of biological molecules. Protein isoforms have profound influences on cellular and tissue physiology, for example, by shaping neuronal connections, enhancing insulin secretion by pancreatic beta cells and allowing for alternative viral defense strategies in stem cells. More broadly, alternative splicing enables repurposing proteins from one context to another and thereby contributes to both the evolution of new traits as well as the creation of disease-specific interactomes that drive pathological phenotypes. In this Review, we highlight this universal character of alternative splicing as a central regulator of protein function with implications for almost every biological process.

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Fig. 1: AS-based changes to protein structure can modulate interactions in eight major ways.
Fig. 2: The types of protein–non-protein interactions that are modulated by AS.
Fig. 3: The range of functional diversification of protein isoforms created by AS.

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Data availability

The data analyzed (and/or generated) during the current study are included within the paper and its Supplementary Information or are available from the corresponding author upon request.

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Acknowledgements

We thank B.J. Blencowe and J.S. Mattick for their critical reading of and helpful comments on the manuscript as well as all members of the Neurotranscriptomics Lab at the Garvan Institute of Medical Research for fruitful discussions on AS’s impact on proteins. P.K.-H. was supported by a University International Postgraduate Award scholarship from the University of New South Wales and a Peter & Emma Thomsens legat (stipend). R.J.W. was supported by the E.P. Oldham—Viertel Senior Medical Fellowship, Cancer Council NSW, the Scrimshaw Family Foundation and an NSW Health grant.

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Authors and Affiliations

  1. EMBL Australia, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    Peter Kjer-Hansen & Robert J. Weatheritt

  2. St. Vincent Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia

    Peter Kjer-Hansen

  3. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia

    Robert J. Weatheritt

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P.K.-H. and R.J.W. jointly conceived, wrote and edited this Review.

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Nature Structural & Molecular Biology thanks Chien-Ling Lin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Dimitris Typas, in collaboration with the Nature Structural & Molecular Biology team.

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Supplementary Table 1

This file contains all examples given in the text as well as additional examples of how AS shapes protein interactions with non-proteins.

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Kjer-Hansen, P., Weatheritt, R.J. The function of alternative splicing in the proteome: rewiring protein interactomes to put old functions into new contexts. Nat Struct Mol Biol 30, 1844–1856 (2023). https://doi.org/10.1038/s41594-023-01155-9

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