The Structure of the N-Terminal Domain of the Fragile X Mental Retardation Protein: A Platform for Protein-Protein Interaction

Abstract

FMRP, whose lack of expression causes the X-linked fragile X syndrome, is a modular RNA binding protein thought to be involved in posttranslational regulation. We have solved the structure in solution of the N-terminal domain of FMRP (NDF), a functionally important region involved in multiple interactions. The structure consists of a composite fold comprising two repeats of a Tudor motif followed by a short alpha helix. The interactions between the three structural elements are essential for the stability of the NDF fold. Although structurally similar, the two repeats have different dynamic and functional properties. The second, more flexible repeat is responsible for interacting both with methylated lysine and with 82-FIP, one of the FMRP nuclear partners. NDF contains a 3D nucleolar localization signal, since destabilization of its fold leads to altered nucleolar localization of FMRP. We suggest that the NDF composite fold determines an allosteric mechanism that regulates the FMRP functions.

A Tandem of SH3-like Domains Participates in RNA Binding in KIN17, a Human Protein Activated in Response to Genotoxics

“…The tandem Tudor domain of human 53BP1, 43,44 the tandem Tudor domain of FMRP, 45 the double chromodomains of human CHD1 46 and the double The rmsd values are calculated on 51 C α atoms for subdomains A (spanning residues 284-334 of the hKIN17 sequence) and 52 C α atoms for subdomains B (spanning residues 340-391 of the hKIN17 sequence). Tudor domain of JMJD2A 47 were all reported to bind to methylated peptides through a conserved aromatic cage.…”

The amino-terminal structure of human fragile X mental retardation protein obtained using precipitant-immobilized imprinted polymers

“…Bioinformatics analysis shows that the C-terminus of FMRPD is a highly flexible long loop 5,20 . piMIPs were used to obtain highquality single crystals of FMRPD.…”

“…The molecular replacement method was used successfully with the structure of FXR1 (Protein Data Bank (PDB) accession number 3O8V) 21 as the model to solve the human FMRPD structure after this approach failed using the previously reported FMRP NMR structure (residues: 1 À 134, PDB: 2BKD) 5 and other Tudor proteins as the search model. The final structure of the human FMRPD determined in this study contains four protein molecules (residues 1 À 200; Fig.…”

“…3b, yellow), Tudor2 (also termed NDF2 (ref. 5), residues 61 À 108; Fig. 3b, blue) and a novel KH0 domain (Fig.…”

“…Therefore, FMRP is an important drug target in protecting against influenza. Nonetheless, because of the highly flexibility, only two segments of FMRP's structure (1 À 134 and 216 À 404 residues) have been characterized structurally 5,6 . The most powerful method for determining protein structure is X-ray crystallography, which relies on the availability of high-quality single crystals 7 .…”