title: Structure-function studies of FMRP RGG peptide recognition of an RNA duplex-quadruplex junction.
abstract: We have determined the solution structure of the complex between an arginine-glycine-rich RGG peptide from the human fragile X mental retardation protein (FMRP) and an in vitro-selected guanine-rich (G-rich) sc1 RNA. The bound RNA forms a newly discovered G-quadruplex separated from the flanking duplex stem by a mixed junctional tetrad. The RGG peptide is positioned along the major groove of the RNA duplex, with the G-quadruplex forcing a sharp turn of R(10)GGGGR(15) at the duplex-quadruplex junction. Arg10 and Arg15 form cross-strand specificity-determining intermolecular hydrogen bonds with the major-groove edges of guanines of adjacent Watson-Crick G•C pairs. Filter-binding assays on RNA and peptide mutations identify and validate contributions of peptide-RNA intermolecular contacts and shape complementarity to molecular recognition. These findings on FMRP RGG domain recognition by a combination of G-quadruplex and surrounding RNA sequences have implications for the recognition of other genomic G-rich RNAs.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. phantuan@ntu.edu.sg
authors.forename: Anh Tuân
authors.initials: AT
authors.lastname: Phan
authors.forename: Vitaly
authors.initials: V
authors.lastname: Kuryavyi
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Darnell
authors.forename: Alexander
authors.initials: A
authors.lastname: Serganov
authors.forename: Ananya
authors.initials: A
authors.lastname: Majumdar
authors.forename: Serge
authors.initials: S
authors.lastname: Ilin
authors.forename: Tanya
authors.initials: T
authors.lastname: Raslin
authors.forename: Anna
authors.initials: A
authors.lastname: Polonskaia
authors.forename: Cynthia
authors.initials: C
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Clain
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
mesh_terms: D001665:Binding Sites; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000737:chemistry* / Q000502:physiology; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D006147:Guanine; D012313:RNA; C497683:FMR1 protein, human