An extended U2AF65–RNA-binding domain recognizes the 3′ splice site signal

Anant A. Agrawal, Enea Salsi, Rakesh Chatrikhi, Steven Henderson, Jermaine L. Jenkins, Michael R. Green, Dmitri N. Ermolenko and Clara L. Kielkopf ()
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Anant A. Agrawal: University of Rochester School of Medicine and Dentistry
Enea Salsi: University of Rochester School of Medicine and Dentistry
Rakesh Chatrikhi: University of Rochester School of Medicine and Dentistry
Steven Henderson: University of Rochester School of Medicine and Dentistry
Jermaine L. Jenkins: University of Rochester School of Medicine and Dentistry
Michael R. Green: Howard Hughes Medical Institute and Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School
Dmitri N. Ermolenko: University of Rochester School of Medicine and Dentistry
Clara L. Kielkopf: University of Rochester School of Medicine and Dentistry

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract How the essential pre-mRNA splicing factor U2AF65 recognizes the polypyrimidine (Py) signals of the major class of 3′ splice sites in human gene transcripts remains incompletely understood. We determined four structures of an extended U2AF65–RNA-binding domain bound to Py-tract oligonucleotides at resolutions between 2.0 and 1.5 Å. These structures together with RNA binding and splicing assays reveal unforeseen roles for U2AF65 inter-domain residues in recognizing a contiguous, nine-nucleotide Py tract. The U2AF65 linker residues between the dual RNA recognition motifs (RRMs) recognize the central nucleotide, whereas the N- and C-terminal RRM extensions recognize the 3′ terminus and third nucleotide. Single-molecule FRET experiments suggest that conformational selection and induced fit of the U2AF65 RRMs are complementary mechanisms for Py-tract association. Altogether, these results advance the mechanistic understanding of molecular recognition for a major class of splice site signals.

Date: 2016
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DOI: 10.1038/ncomms10950

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