Analysis of choroideraemia gene

Fodor, E; Lee, Robert T.; O’Donnell, James J.

doi:10.1038/351614b0

Cited by 24 publications

(1 citation statement)

References 8 publications

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“…Further insight into the function of CHM came with the realization that it shows sequence similarity ( ‫ف‬ 30%) to guanine nucleotide dissociation inhibitor (GDI) involved in the recycling of small GTPases belonging to the Rab gene family (Fodor and Lee, 1991). GDI is largely specific for only the prenylated form and, therefore, does not participate in delivery of nascent Rab to the catalytic subunits of RabGG transferase (Sasaki et al, 1990;Alexandrov et al, 1994;Wu et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis for Rab Prenylation

Alory

Balch

2000

The Journal of Cell Biology

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Rab escort proteins (REP) 1 and 2 are closely related mammalian proteins required for prenylation of newly synthesized Rab GTPases by the cytosolic heterodimeric Rab geranylgeranyl transferase II complex (RabGG transferase). REP1 in mammalian cells is the product of the choroideremia gene (CHM). CHM/REP1 deficiency in inherited disease leads to degeneration of retinal pigmented epithelium and loss of vision. We now show that amino acid residues required for Rab recognition are critical for function of the yeast REP homologue Mrs6p, an essential protein that shows 50% homology to mammalian REPs. Mutant Mrs6p unable to bind Rabs failed to complement growth of a mrs6Δ null strain and were found to be dominant inhibitors of growth in a wild-type MRS6 strain. Mutants were identified that did not affect Rab binding, yet prevented prenylation in vitro and failed to support growth of the mrs6Δ null strain. These results suggest that in the absence of Rab binding, REP interaction with RabGG transferase is maintained through Rab-independent binding sites, providing a molecular explanation for the kinetic properties of Rab prenylation in vitro. Analysis of the effects of thermoreversible temperature-sensitive (mrs6 ts) mutants on vesicular traffic in vivo showed prenylation activity is only transiently required to maintain normal growth, a result promising for therapeutic approaches to disease.

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Section: Introductionmentioning

confidence: 99%

Molecular Basis for Rab Prenylation

Alory

Balch

2000

The Journal of Cell Biology

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The yeast protein Mrs6p, a homologue of the rabGDI and human choroideraemia proteins, affects cytoplasmic and mitochondrial functions

et al. 1994

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MRS6 is a newly-identified gene in the yeast Saccharomyces cerevisiae. Its product Mrs6p shows significant homology to the mammalian GDP dissociation inhibitor (GDI) of Rab/Ypt-type small G proteins and to the human choroideraemia protein (CHM), the component A of Rab-specific GGTase II. The interaction of Mrs6p with G proteins is indicated by our observation that the MRS6 gene suppresses the effect of a temperature-sensitive ypt1 mutation. Disruption of the MRS6 gene is lethal to haploid yeast cells. This is consistent with the notion that Mrs6p is interacting with Rab/Ypt-type small G proteins, which are known to have essential functions in vesicular transport. Unexpectedly, the MRS6 gene product also affects mitochondrial functions as revealed by the facts that high-copy numbers of MRS6 (1) suppress the pet- phenotype of mrs2-1 mutant strains and (2) cause a weak pet- phenotype in wild-type strains. We conclude from these results that the MRS6 gene product has a vital function in connection with Rab/Ypt-type proteins in the cytoplasm and, in addition, affects mitochondrial functions.

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Evolutionary conservation and genomic organization of XAP-4, an Xq28 located gene coding for a human rab GDP-dissociation inhibitor (GDI)

et al. 1994

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After the development of efficient methods for the construction of transcription maps of defined genomic regions, the rate-limiting step in the analysis of the coding potentials of these regions is the elucidation of function of the novel genes and the examination of their possible involvement in hereditary diseases localized to the region. This can be greatly facilitated by the detection of sequence homology to a gene of known function. XAP-4 is one of the genes identified in the G6PD region of the human Xq28 by direct cDNA selection. The rapid assembly of this gene and the determination of its function was possible because of its sequence homology with the bovine smg p25A/rab3A GDP dissociation inhibitor (GDI). Sequence comparison with other GDIs in the databases has revealed that XAP-4 belongs to one of at least two distinct classes of mammalian rab GDIs. The rab GDIs, which play an important role in the regulation of cellular transport, are highly evolutionarily conserved, as are several other genes identified in the neighborhood of XAP-4. This genomic region is very gene dense, and all the cDNA clones from the approximately 2.5-kb-long transcript of XAP-4 map to a single 7.5-kb genomic EcoRI fragment. The genomic organization of XAP-4 has been examined to determine the distribution of the exonic sequences within this short segment of genomic DNA. It was found that, similar to several other genes from the region, XAP-4 is split into exons of average size, which are interrupted by very short introns.

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Analysis of choroideraemia gene

Cited by 24 publications

References 8 publications

Molecular Basis for Rab Prenylation

Molecular Basis for Rab Prenylation

The yeast protein Mrs6p, a homologue of the rabGDI and human choroideraemia proteins, affects cytoplasmic and mitochondrial functions

Evolutionary conservation and genomic organization of XAP-4, an Xq28 located gene coding for a human rab GDP-dissociation inhibitor (GDI)

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