A sequential binding mechanism for 5' splice site recognition and modulation for the human U1 snRNP.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 Oct 2024
10 Oct 2024
Historique:
received:
01
06
2024
accepted:
30
09
2024
medline:
11
10
2024
pubmed:
11
10
2024
entrez:
10
10
2024
Statut:
epublish
Résumé
Splice site recognition is essential for defining the transcriptome. Drugs like risdiplam and branaplam change how human U1 snRNP recognizes particular 5' splice sites (5'SS) and promote U1 snRNP binding and splicing at these locations. Despite the therapeutic potential of 5'SS modulators, the complexity of their interactions and snRNP substrates have precluded defining a mechanism for 5'SS modulation. We have determined a sequential binding mechanism for modulation of -1A bulged 5'SS by branaplam using a combination of ensemble kinetic measurements and colocalization single molecule spectroscopy (CoSMoS). Our mechanism establishes that U1-C protein binds reversibly to U1 snRNP, and branaplam binds to the U1 snRNP/U1-C complex only after it has engaged with a -1A bulged 5'SS. Obligate orders of binding and unbinding explain how reversible branaplam interactions cause formation of long-lived U1 snRNP/5'SS complexes. Branaplam targets a ribonucleoprotein, not only an RNA duplex, and its action depends on fundamental properties of 5'SS recognition.
Identifiants
pubmed: 39389991
doi: 10.1038/s41467-024-53124-5
pii: 10.1038/s41467-024-53124-5
doi:
Substances chimiques
Ribonucleoprotein, U1 Small Nuclear
0
RNA Splice Sites
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8776Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM136261
Pays : United States
Informations de copyright
© 2024. The Author(s).
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