A nuclear role for the Fragile X mental retardation protein.

Fridell, Robert A.; Benson, R. Edward; Hua, Jian; Bogerd, Hal P.; Cullen, Bryan R.

doi:10.1002/j.1460-2075.1996.tb00924.x

Cited by 118 publications

(72 citation statements)

References 39 publications

(141 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A short stretch of amino acids (Leu52-Leu61) of the Scpl60p sequence exhibits similarity to the leucine-rich nuclear export signals from human immunodeficiency virus (HIV)-l Rev [30] and FMRP [31], with the reservation that the last two leucines of the Scpl6Op sequence are separated by two residues instead of only one as in the consensus sequence for nuclear export proposed by Bogerd et al [32]. No such signal exists at the corresponding positions of the vigilins or of C08H9.2.…”

Section: Scpl6op Contains 14 Kh Domains and Is The Yeast Homologue Ofmentioning

confidence: 99%

Purification and Nucleic‐Acid‐Binding Properties of a Saccharomyces Cerevisiae Protein Involved in the Control of Ploidy

Weber¹,

Wernitznig²,

Hager³

et al. 1997

European Journal of Biochemistry

View full text Add to dashboard Cite

Scpl6Op (Succhuromyces cerevisiae protein involved in the control of ploidy), a polypeptide with a molecular mass of around 160 kDa, is associated with the nuclear envelope and the endoplasmic reticulum. The most noteworthy phenotype of SCP160 deletion mutants is a decrease in viability and an increased number of chromosomes in the surviving cells [Wintersberger, U., Kiihne, C. & Karwan, A. (1995) Yeast 11, 929-9441. Scpl6Op contains 14 KH domains, conserved motifs that have lately been identified in a variety of RNA-binding proteins. In this report, we demonstrate that the Scpl6Op sequence shows nearly perfect colinearity with the putative gene product of C08H9.2 from the nematode Cuenorhubditis elegans as well as with the vigilins, vertebrate RNA-binding proteins with a cellular location similar to that of Scpl6Op. Moreover, we found that Scpl6Op contains a potential nuclear-export signal (NES) near its N-terminus and a potential nuclear-localization signal (NLS) between KH domains 3 and 4. To determine whether the protein is able to bind to RNA, we purified Scpl6Op from yeast cell extract by DNA-cellulose and anti-Scpl6Op affinity chromatography. In northwestern blotting experiments, the electrophoretically homogeneous protein bound to ribohomopolymers and ribosomal RNA as well as to single-stranded and double-stranded DNA. Subcellular fractionation studies revealed that the major part of Scpl6Op is membrane associated via ionic interactions and can be released from the membrane fraction under conditions that lead to a dissociation of ribosomes. Together, our findings suggest that Scpl6Op is the yeast homologue of the vigilins, and point to a role for Scpl6Op in nuclear RNA export o r in RNA transport within the cytoplasm.Keywords: KH domain ; nucleic-acid-binding protein ; RNA transport.A multitude of RNA-binding proteins play key roles in the regulation of gene expression. Characterization of these proteins has led to the identification of several RNA-binding motifs [ 1, 21. One of these motifs, the KH domain (for K protein homology), was first identified as a repeated sequence in human hnRNP K protein [3]. According to secondary-structure prediction and NMR spectroscopy, the KH domain folds into a globular structure consisting of an antiparallel three-stranded P-sheet connected by two helical regions and an appended C-terminal helix [4]. Based on this secondary structure, it has been proposed that positively charged residues in the loop between the first two helices form a potential surface for contact with RNA [5] [I 8-20]. A direct in vivo interaction between the KH motif of ribosomal protein S3 and rRNA was demonstrated by cross-linking studies in 30s and 50s ribosomal subunits of E. coli and Bacillus stearothermophilus [9]. We have recently reported the cloning of SCP160 (S. cerevisiae gene involved in the control of ploidy). The gene, which is located on chromosome X, codes for a polypeptide with a molecular mass of around 160 kDa, Scpl6Op. Indirect immunofluorescence experiments with anti-Scpl60p ...

show abstract

Section: Scpl6op Contains 14 Kh Domains and Is The Yeast Homologue Ofmentioning

confidence: 99%

Purification and Nucleic‐Acid‐Binding Properties of a Saccharomyces Cerevisiae Protein Involved in the Control of Ploidy

Weber¹,

Wernitznig²,

Hager³

et al. 1997

European Journal of Biochemistry

View full text Add to dashboard Cite

show abstract

“…The recent demonstration that Drosophila fragile X-related protein (Fmr1; previously dFXR) interacts with components of the RNA interference (RNAi) machinery raises the possibility that Fmr1/FMR1 may also function as part of a gene-silencing mechanism (Ishizuka et al, 2002;Caudy et al, 2002). FMR1 is highly expressed in neuronal perikaryon and dendrites and shuttles between the nucleus and the cytosol (Devys et al, 1993;Fridell et al, 1996;Feng et al, 1997b). Studies of individuals with fragile X syndrome, Fmr1 knockout mice and cultured neurons, although not entirely consistent Fragile X syndrome is caused by loss-of-function mutations in the fragile X mental retardation 1 gene.…”

Section: Introductionmentioning

confidence: 99%

Control of dendritic development by theDrosophila fragile X-relatedgene involves the small GTPase Rac1

et al. 2003

View full text Add to dashboard Cite

Fragile X syndrome is caused by loss-of-function mutations in the fragile X mental retardation 1 gene. How these mutations affect neuronal development and function remains largely elusive. We generated specific point mutations or small deletions in the Drosophila fragile X-related (Fmr1) gene and examined the roles of Fmr1 in dendritic development of dendritic arborization (DA) neurons in Drosophila larvae. We found that Fmr1 could be detected in the cell bodies and proximal dendrites of DA neurons and that Fmr1loss-of-function mutations increased the number of higher-order dendritic branches. Conversely, overexpression of Fmr1 in DA neurons dramatically decreased dendritic branching. In dissecting the mechanisms underlying Fmr1 function in dendrite development, we found that the mRNA encoding small GTPase Rac1 was present in the Fmr1-messenger ribonucleoprotein complexes in vivo. Mosaic analysis with a repressor cell marker (MARCM) and overexpression studies revealed that Rac1 has a cell-autonomous function in promoting dendritic branching of DA neurons. Furthermore, Fmr1 and Rac1 genetically interact with each other in controlling the formation of fine dendritic branches. These findings demonstrate that Fmr1 affects dendritic development and that Rac1 is partially responsible for mediating this effect.

show abstract

“…An even more striking nuclear retention is observed for the mutated FMRP containing the Ile304Asn amino acid substitution in the second KH domain (Tamanini et al, 1999). Even if a domain similar to an NLS has been identified in exon 14, overexpressed FMRP lacking exon 14 can indeed enter the nucleus (Fridell et al, 1996;Bardoni et al, 1997). Interestingly, this exon is alternatively spliced, and certain FMRP isoforms are therefore excluded from the nucleus (Sittler et al, 1996).…”

Section: Undiscovered Roles Of Fmrpmentioning

confidence: 98%

Molecular Insights into Mental Retardation: Multiple Functions for the Fragile X Mental Retardation Protein?

Zalfa

Bagni

2004

Current Issues in Molecular Biology

View full text Add to dashboard Cite

Mental retardation is a frequent cause of intellectual and physical impairment. Several genes associated with mental retardation have been mapped to the X chromosome, among them, there is FMR1. The absence of or mutation in the Fragile Mental Retardation Protein, FMRP, is responsible for the Fragile X syndrome. FMRP is an RNA binding protein that shuttles between the nucleus and the cytoplasm. FMRP binds to several mRNAs including its own mRNA at a sequence region containing a G quartet structure. Some of the candidate downstream genes recently identified encode for synaptic proteins. Neuronal studies indicate that FMRP is located at synapses and loss of FMRP affects synaptic plasticity. At the synapses, FMRP acts as a translational repressor and in particular regulates translation of specific dendritic mRNAs, some of which encode cytoskeletal proteins and signal transduction molecules. This action occurs via a ribonucleoprotein complex that includes a small dendritic non-coding neuronal RNA that determines the specificity of FMRP function via a novel mechanism of translational repression. Since local protein synthesis is required for synaptic development and function, this role of FMRP likely underlies some of the behavioural and developmental symptoms of FRAXA patients. Finally we review recent work on the Drosophila system that connects cytoskeleton remodelling and FMRP function.

show abstract

A nuclear role for the Fragile X mental retardation protein.

Cited by 118 publications

References 39 publications

Purification and Nucleic‐Acid‐Binding Properties of a Saccharomyces Cerevisiae Protein Involved in the Control of Ploidy

Purification and Nucleic‐Acid‐Binding Properties of a Saccharomyces Cerevisiae Protein Involved in the Control of Ploidy

Control of dendritic development by theDrosophila fragile X-relatedgene involves the small GTPase Rac1

Molecular Insights into Mental Retardation: Multiple Functions for the Fragile X Mental Retardation Protein?

Contact Info

Product

Resources

About