Title | Discrimination of common and unique RNA-binding activities among Fragile X mental retardation protein paralogs. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Darnell JC, Fraser CE, Mostovetsky O, Darnell RB |
Journal | Hum Mol Genet |
Volume | 18 |
Issue | 17 |
Pagination | 3164-77 |
Date Published | 2009 Sep 01 |
ISSN | 1460-2083 |
Keywords | Amino Acid Sequence, Animals, Fragile X Mental Retardation Protein, Fragile X Syndrome, G-Quadruplexes, Humans, Kinetics, Mice, Molecular Sequence Data, Neurons, Polyribosomes, Protein Binding, Protein Structure, Tertiary, RNA-Binding Proteins, Sequence Alignment |
Abstract | Fragile X mental retardation is caused by loss-of-function of a single gene encoding FMRP, an RNA-binding protein that harbors three canonical RNA-binding domains, two KH-type and one RGG box. Two autosomal paralogs of FMRP, FXR1P and FXR2P, are similar to FMRP in their overall structure, including the presence of putative RNA-binding domains, but to what extent they provide functional redundancy with FMRP is unclear. Although FMRP has been characterized as a polyribosome-associated regulator of translation, less is known about the functions of FXR1P and FXR2P. For example, FMRP binds intramolecular G-quadruplex and kissing complex RNA (kcRNA) ligands via the RGG box and KH2 domain, respectively, although the RNA ligands of FXR1P and FXR2P are unknown. Here we demonstrate that FXR1P and FXR2P KH2 domains bind kcRNA ligands with the same affinity as the FMRP KH2 domain although other KH domains do not. RNA ligand recognition by this family is highly conserved, as the KH2 domain of the single Drosophila ortholog, dFMRP, also binds kcRNA. kcRNA was able to displace FXR1P and FXR2P from polyribosomes as it does for FMRP, and this displacement was FMRP-independent. This suggests that all three family members recognize the same binding site on RNA mediating their polyribosome association, and that they may be functionally redundant with regard to this aspect of translational control. In contrast, FMRP is unique in its ability to recognize G-quadruplexes, suggesting the FMRP RGG domain may play a non-redundant role in the pathophysiology of the disease. |
DOI | 10.1093/hmg/ddp255 |
Alternate Journal | Hum. Mol. Genet. |
PubMed ID | 19487368 |
PubMed Central ID | PMC2722981 |
Grant List | 5R01 HD40647 / HD / NICHD NIH HHS / United States NS40955 / NS / NINDS NIH HHS / United States / / Howard Hughes Medical Institute / United States R01 HD40647 / HD / NICHD NIH HHS / United States R01S NS34389 / NS / NINDS NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:10pm