Molecular Basis for Rab Prenylation

Alory, Christelle; Balch, William E.

doi:10.1083/jcb.150.1.89

Cited by 56 publications

(54 citation statements)

References 46 publications

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“…In the yeast Saccharomyces cerevisiae, for example, the homolog of REP1 (MRS6) is an essential gene (18). In its absence, Rab GTPases remain unmodified and accumulate in the cytosol (24), precluding their conversion into active, GTP-bound forms and thus preventing the recruitment of their effectors to the membrane surface. The cytoplasmic inclusions in chm mutant cells might represent accumulations of unprenylated Rabs or other proteins whose processing is interrupted by the absence of prenylated Rabs.…”

Section: Discussionmentioning

confidence: 99%

“…This may be explained if hair cells are especially susceptible to reduced levels of this protein, whereas other cell types are able to function for a time with a limited amount of maternally derived transcript or protein. Prenylated Rabs are known to be very stable, and a transient supply of correctly folded MRS6 is enough to maintain normal growth rates in yeast (24).…”

Section: Discussionmentioning

confidence: 99%

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Mutation of the zebrafish choroideremia gene encoding Rab escort protein 1 devastates hair cells

Starr

Kappler²,

Chan³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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To identify genes important for hair-cell function, we conducted a mutagenic screen in zebrafish. Larvae from one mutant line, ru848, were unresponsive to acoustic stimuli and unable to balance. The mutation results in a 90% reduction in hair-cell number and partial retinal degeneration by 5 days postfertilization. We localized the recessive ru848 mutation by positional cloning to the zebrafish homolog of the human Choroideremia gene, which encodes Rab escort protein 1. This protein is essential for the normal prenylation of Rabs. Mutations in the human gene induce choroideremia, a disease marked by slow-onset degeneration of rod photoreceptors and retinal pigment epithelial cells. The degenerative phenotype resulting from a null mutation in the zebrafish gene indicates that hair cells and retinal cells require Rab escort protein 1 for survival. The internal ear, one of the most complex organs of a vertebrate organism, converts mechanical stimuli into neuronal responses. The task of mechanotransduction is accomplished by the ear's sensory receptor, the hair cell. The lateralline organs of fishes and aquatic amphibians also use this receptor to detect water movements. Despite our detailed knowledge of the hair cell's mechanical and electrical properties (1), our progress in understanding its development and operation has been impeded by our lack of knowledge of the relevant molecular components.One strategy used to identify genes important for hair-cell function is the investigation of their loss-of-function phenotypes, deafness and disequilibrium. The principal advantage of such a genetic approach is that detailed characterization of the mutant phenotype provides explicit clues about the role of the gene involved. Large-scale mutagenesis screens for mechanosensory mutants in Drosophila melanogaster and Caenorhabditis elegans have identified molecules critical for vibration and touch sensitivity (2-4). The absence of hair cells in invertebrates, however, makes screens specific to hair-cell defects impossible in these organisms.To identify important proteins in the hair cell, we have created point mutations randomly throughout the zebrafish genome and screened for impairment of ear and lateral-line-organ development and function. Several of the identified mutations have been subjected to further phenotypic analysis and genetic mapping and cloning. We report here the characterization of a mutation that identifies an important process in hair cells and serves as a model of degenerative disease in the human retina. Materials and Methods ru848Identification and Breeding. Zebrafish were maintained in aquaria (Marine Biotech, Beverly, MA) according to published protocols (5). Embryos were raised in a 28.5°C incubator in facility water containing 1 g͞ml methylene blue and staged as described (6). Male fish of the TL strain were mutagenized with ethylnitrosourea and bred for three generations to create homozygous F 3 larvae (7) that were screened for hearing defects by observing their response to a sharp tap on the side o...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mutation of the zebrafish choroideremia gene encoding Rab escort protein 1 devastates hair cells

Starr

Kappler²,

Chan³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Rab GTPases are small proteins anchored to membranes by geranylgeranyl hydrocarbon chains (Alory & Balch, 2000). They act as molecular switches by alternatively binding to GDP (inactive form) and GTP (active form).…”

Section: Conservation Of Intracellular Traffic and Exocytosis Pathwaysmentioning

confidence: 99%

A genomic analysis of transcytosis in the pea aphid, Acyrthosiphon pisum, a mechanism involved in virus transmission

Tamborindeguy

Monsion

Brault

et al. 2010

Insect Molecular Biology

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“…Several effector proteins alter either the state of phosphorylation or the intracytoplasmic location of Rab proteins and thus modulate their biological activity (25). The first modification refers to a posttranslational covalent addition of two 20-carbon isoprenoid geranyl-geranyl groups to free cysteine residues near or at the carboxy terminus (2). Isoprenylation facilitates association of Rab proteins with membranebound compartments and allows their localization to the cytoplasmic surface of distinct exocytic and endocytic organelles.…”

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confidence: 99%

Interactions of Rotavirus VP4 Spike Protein with the Endosomal Protein Rab5 and the Prenylated Rab Acceptor PRA1

Enouf

Chwetzoff

Trugnan

et al. 2003

J Virol

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Rotavirus spike protein VP4 is implicated in several important functions, such as cell attachment, penetration, hemagglutination, neutralization, virulence, and host range. It is present at the plasma membrane and colocalizes with the cytoskeleton in infected cells. We looked for cellular partners responsible for the localization of VP4 by two-hybrid screening of a monkey CV1 cell cDNA library. In the screen we isolated repeatedly three cDNAs encoding either two isoforms (a and c) of Rab5 protein or the prenylated Rab acceptor (PRA1). The small GTPase Rab5 is a molecule regulating the vesicular traffic and the motility of early endosomes along microtubules. Rab5 interacts with a large number of effectors, in particular with PRA1. Interactions of VP4 with both partners, Rab5 and PRA1, were confirmed by coimmunoprecipitation from infected-or transfectedcell lysates. Interaction of Rab5 and PRA1 was restricted to free VP4, since neither triple-layered particles nor NSP4-VP4-VP7 heterotrimeric complexes could be coprecipitated. Site-directed and deletion mutants of VP4 were used to map a VP4 domain(s) interacting with Rab5 or PRA1. Of the 10 mutants tested, 2 interacted exclusively with a single partner. In contrast, the domain extending from amino acids 560 to 722 of VP4 is essential for both interactions. These results suggest that Rab5 and PRA1 may be involved in the localization and trafficking of VP4 in infected cells.Rotaviruses are the leading cause of severe gastroenteritis in young children worldwide (24). Structural and biochemical analyses show that rotaviruses are large, icosahedral particles consisting of three concentric capsid layers surrounding a genome of 11 segments of double-stranded RNA (15, 45). VP4 is a nonglycosylated protein and forms spikes that project from the rotavirus surface. Trypsin cleavage of VP4 into the fragments VP8* and VP5* is required for viral infectivity and stabilization of the spikes (11, 30). VP4 has been implicated in several important functions, such as cell attachment, penetration, hemagglutination, neutralization, and virulence (10,17,26,32). It has been shown previously that VP5*, which includes a conserved hydrophobic region located between amino acids (aa) 384 and 401 of VP4, is a specific membrane-permeabilizing protein and could play a role in the cellular entry of rotaviruses (12). Heterotrimers consisting of VP4, NSP4, and VP7 may participate in the budding of the single-shelled particles into the lumen of the endoplasmic reticulum, where maturation to double-shelled particles seems to occur (33, 39).Rab proteins are a family of Ras-related low-molecularweight monomeric GTP-binding proteins (ϳ20 to 29 kDa) which are key regulators of vesicular transport within eukaryotic cells (7). Several effector proteins alter either the state of phosphorylation or the intracytoplasmic location of Rab proteins and thus modulate their biological activity (25). The first modification refers to a posttranslational covalent addition of two 20-carbon isoprenoid geranyl-geranyl gro...

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Molecular Basis for Rab Prenylation

Cited by 56 publications

References 46 publications

Mutation of the zebrafish choroideremia gene encoding Rab escort protein 1 devastates hair cells

Mutation of the zebrafish choroideremia gene encoding Rab escort protein 1 devastates hair cells

A genomic analysis of transcytosis in the pea aphid, Acyrthosiphon pisum, a mechanism involved in virus transmission

Interactions of Rotavirus VP4 Spike Protein with the Endosomal Protein Rab5 and the Prenylated Rab Acceptor PRA1

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