Fragile X messenger ribonucleoprotein 1 (FMRP/FMR1), and its paralogues, FXR1 and FXR2 (RNA-binding protein FXR1 and 2, respectively), comprise a family of RNA-binding proteins [].FMR1 protein is a multifunctional polyribosome-associated protein that plays a central role in neuronal development and synaptic plasticity. It regulates alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of a subset of mRNAs [, , ]. FMR1 is thought to bind target mRNA in the nucleus to form a ribonucleoprotein complex which is transported to dendrites and spines []. It is also required for ovary development and function []. FMR1 has also been shown to interact with components of the miRNA pathway []. A large expansion of the CGG trinucleotide repeat in the 5'-untranslated region of the FMR1 gene causes Fragile X syndrome (FXS), an inherited developmental disorder that causes a broad range of intellectual and physical challenges [].FXR1 and FXR2 interact with FMR1 and seem to have a related role; therefore they are likely to play important roles in the function of FMR1 and in the pathogenesis of the FXS syndrome [, ]. FXR1 is highly expressed in vertebrates muscle cells and is required for proper development of this tissue [, ].
CGG triplet repeat-binding protein 1 (CGGBP1) is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs []. CGGBP1 mitigates cytosine methylation at repetitive DNA sequences []. It also functions in DNA damage/repair and telomere metabolism []. There are indications that it may be involved in mRNA metabolism []. CGGBP1 ensures CTCF occupancy preferentially on repeats over canonical CTCF motifs, being a regulator of CTCF and its binding sites in interspersed repeats [].CGGBP1/p20 is known to bind to nonmethylated 5'-d(CGG)(n)-3' trinucleotide repeats in the in the promoter of the fragile X messenger ribonucleoprotein 1 (FMR1/FMRP) gene [, ], although it seems not to have a direct effect on FMR1 transcription [].
The K homology (KH) domain was first identified in the human heterogeneous nuclear ribonucleoprotein (hnRNP) K. An evolutionarily conserved sequence of around 70 amino acids, the KH domain is present in a wide variety of nucleic acid-binding proteins. The KH domain binds RNA, and can function in RNA recognition []. It is found in multiple copies in several proteins, where they can function cooperatively or independently. For example, in the AU-rich element RNA-binding protein KSRP, which has 4 KH domains, KH domains 3 and 4 behave as independent binding modules to interact with different regions of the AU-rich RNA targets []. The solution structure of the first KH domain of FMR1 []and of the C-terminal KH domain of hnRNP K []determined by nuclear magnetic resonance(NMR) revealed a β-α-α-β-β-α structure. Proteins containing KH domains include:Bacterial and organelle PNPases [].Archaeal and eukaryotic exosome subunits [].Eukaryotic and prokaryotic RS3 ribosomal proteins [].Vertebrate Fragile X messenger ribonucleoprotein 1 (FMR1) [].Vigilin, which has 14 KH domains [].AU-rich element RNA-binding protein KSRP.hnRNP K, which contains 3 KH domains.Human onconeural ventral antigen-1 (NOVA-1) [].According to structural analyses [, , ], the KH domain can be separated in two groups - type 1 and type 2.
