Structure-function studies of FMRP RGG peptide recognition of an RNA duplex-quadruplex junction

• DOI: 10.1038/nsmb.2064
• Publication Date: 2011-06-05T17:19:09Z
• Authors: Anh Tuân Phan; Vitaly Kuryavyi; Jennifer C Darnell; Alexander Serganov; Ananya Majumdar; Serge Ilin; Tanya Raslin; Anna Polonskaia; Cynthia Chen; David Clain; Robert B Darnell; Dinshaw J Patel
• Keywords: Models, Molecular; 0303 health sciences; Binding Sites; Guanine; Hydrogen Bonding; Article; Protein Structure, Tertiary; G-Quadruplexes; Fragile X Mental Retardation Protein; Structure-Activity Relationship; 03 medical and health sciences; Humans; Nucleic Acid Conformation; RNA; Nuclear Magnetic Resonance, Biomolecular

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.