title: Isolated pseudo-RNA-recognition motifs of SR proteins can regulate splicing using a noncanonical mode of RNA recognition.
abstract: Serine/arginine (SR) proteins, one of the major families of alternative-splicing regulators in Eukarya, have two types of RNA-recognition motifs (RRMs): a canonical RRM and a pseudo-RRM. Although pseudo-RRMs are crucial for activity of SR proteins, their mode of action was unknown. By solving the structure of the human SRSF1 pseudo-RRM bound to RNA, we discovered a very unusual and sequence-specific RNA-binding mode that is centered on one α-helix and does not involve the β-sheet surface, which typically mediates RNA binding by RRMs. Remarkably, this mode of binding is conserved in all pseudo-RRMs tested. Furthermore, the isolated pseudo-RRM is sufficient to regulate splicing of about half of the SRSF1 target genes tested, and the bound α-helix is a pivotal element for this function. Our results strongly suggest that SR proteins with a pseudo-RRM frequently regulate splicing by competing with, rather than recruiting, spliceosome components, using solely this unusual RRM.
authors.affiliation: Institute for Molecular Biology and Biophysics, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland.
authors.forename: Antoine
authors.initials: A
authors.lastname: Cléry
authors.forename: Rahul
authors.initials: R
authors.lastname: Sinha
authors.forename: Olga
authors.initials: O
authors.lastname: Anczuków
authors.forename: Anna
authors.initials: A
authors.lastname: Corrionero
authors.forename: Ahmed
authors.initials: A
authors.lastname: Moursy
authors.forename: Gerrit M
authors.initials: GM
authors.lastname: Daubner
authors.forename: Juan
authors.initials: J
authors.lastname: Valcárcel
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
authors.forename: Frédéric H-T
authors.initials: FH
authors.lastname: Allain
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry*; D001665:Binding Sites; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D012326:RNA Splicing; D012694:Serine / Q000737:chemistry*
chemical_list: D011506:Proteins; D012694:Serine; D012313:RNA; D001120:Arginine
keywords: NMR; protein–RNA complex; splicing factor