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Crystal structure reveals specific recognition of a G-quadruplex RNA by a ?-turn in the RGG motif of FMRP.


ABSTRACT: Fragile X Mental Retardation Protein (FMRP) is a regulatory RNA binding protein that plays a central role in the development of several human disorders including Fragile X Syndrome (FXS) and autism. FMRP uses an arginine-glycine-rich (RGG) motif for specific interactions with guanine (G)-quadruplexes, mRNA elements implicated in the disease-associated regulation of specific mRNAs. Here we report the 2.8-Å crystal structure of the complex between the human FMRP RGG peptide bound to the in vitro selected G-rich RNA. In this model system, the RNA adopts an intramolecular K(+)-stabilized G-quadruplex structure composed of three G-quartets and a mixed tetrad connected to an RNA duplex. The RGG peptide specifically binds to the duplex-quadruplex junction, the mixed tetrad, and the duplex region of the RNA through shape complementarity, cation-? interactions, and multiple hydrogen bonds. Many of these interactions critically depend on a type I ?-turn, a secondary structure element whose formation was not previously recognized in the RGG motif of FMRP. RNA mutagenesis and footprinting experiments indicate that interactions of the peptide with the duplex-quadruplex junction and the duplex of RNA are equally important for affinity and specificity of the RGG-RNA complex formation. These results suggest that specific binding of cellular RNAs by FMRP may involve hydrogen bonding with RNA duplexes and that RNA duplex recognition can be a characteristic RNA binding feature for RGG motifs in other proteins.

SUBMITTER: Vasilyev N 

PROVIDER: S-EPMC4593078 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP.

Vasilyev Nikita N   Polonskaia Anna A   Darnell Jennifer C JC   Darnell Robert B RB   Patel Dinshaw J DJ   Serganov Alexander A  

Proceedings of the National Academy of Sciences of the United States of America 20150915 39


Fragile X Mental Retardation Protein (FMRP) is a regulatory RNA binding protein that plays a central role in the development of several human disorders including Fragile X Syndrome (FXS) and autism. FMRP uses an arginine-glycine-rich (RGG) motif for specific interactions with guanine (G)-quadruplexes, mRNA elements implicated in the disease-associated regulation of specific mRNAs. Here we report the 2.8-Å crystal structure of the complex between the human FMRP RGG peptide bound to the in vitro s  ...[more]

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