A multi-factor trafficking site on the spliceosome remodeling enzyme BRR2 recruits C9ORF78 to regulate alternative splicing

Alexandra Bergfort, Marco Preußner, Benno Kuropka, İbrahim Avşar Ilik, Tarek Hilal, Gert Weber, Christian Freund, Tuğçe Aktaş, Florian Heyd and Markus C. Wahl ()
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Alexandra Bergfort: Laboratory of Structural Biochemistry
Marco Preußner: Laboratory of RNA Biochemistry
Benno Kuropka: Laboratory of Protein Biochemistry
İbrahim Avşar Ilik: Max Planck Institute for Molecular Genetics
Tarek Hilal: Laboratory of Structural Biochemistry
Gert Weber: Macromolecular Crystallography
Christian Freund: Laboratory of Protein Biochemistry
Tuğçe Aktaş: Max Planck Institute for Molecular Genetics
Florian Heyd: Laboratory of RNA Biochemistry
Markus C. Wahl: Laboratory of Structural Biochemistry

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The intrinsically unstructured C9ORF78 protein was detected in spliceosomes but its role in splicing is presently unclear. We find that C9ORF78 tightly interacts with the spliceosome remodeling factor, BRR2, in vitro. Affinity purification/mass spectrometry and RNA UV-crosslinking analyses identify additional C9ORF78 interactors in spliceosomes. Cryogenic electron microscopy structures reveal how C9ORF78 and the spliceosomal B complex protein, FBP21, wrap around the C-terminal helicase cassette of BRR2 in a mutually exclusive manner. Knock-down of C9ORF78 leads to alternative NAGNAG 3′-splice site usage and exon skipping, the latter dependent on BRR2. Inspection of spliceosome structures shows that C9ORF78 could contact several detected spliceosome interactors when bound to BRR2, including the suggested 3′-splice site regulating helicase, PRPF22. Together, our data establish C9ORF78 as a late-stage splicing regulatory protein that takes advantage of a multi-factor trafficking site on BRR2, providing one explanation for suggested roles of BRR2 during splicing catalysis and alternative splicing.

Date: 2022
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DOI: 10.1038/s41467-022-28754-2

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