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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a late-Golgi compartment of the yeast Saccharomyces cerevisiae, vacuolar proteins such as carboxypeptidase Y (CPY) are actively sorted away from the secretory pathway and transported to the vacuole via a pre-vacuolar, endosome-like intermediate. The vacuolar protein sorting (vps) mutant vps4 accumulates vacuolar, endocytic and late-Golgi markers in an aberrant multilamellar pre-vacuolar compartment. The VPS4 gene has been cloned and found to encode a 48 kDa protein which belongs to the protein family of AAA-type ATPases. The Vps4 protein was purified and shown to exhibit an N-ethylmaleimide-sensitive ATPase activity. A single amino acid change within the AAA motif of Vps4p yielded a protein that lacked ATPase activity and did not complement the protein sorting or morphological defects of the vps4 delta1 mutant. Indeed, when expressed at normal levels in wild-type cells, the mutant vps4 gene acted as a dominant-negative allele. The phenotypic characterization of a temperature-sensitive vps4 allele showed that the immediate consequence of loss of Vps4p function is a defect in vacuolar protein delivery. In this mutant, precursor CPY was not secreted but instead accumulated in an intracellular compartment, presumably the pre-vacuolar endosome. Electron microscopy revealed that upon temperature shift, exaggerated stacks of curved cisternal membranes (aberrant endosome) also accumulated in the vps4ts mutant. Based on these and other observations, we propose that Vps4p function is required for efficient transport out of the pre-vacuolar endosome.
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PMID:Endosomal transport function in yeast requires a novel AAA-type ATPase, Vps4p. 915 8

Four yeast mutants were isolated in a screen for dominant-negative vacuolar protein-sorting mutants, secreting a carboxypeptidase Y-invertase hybrid protein. In addition to defects in the sorting/transport of soluble vacuolar hydrolases, the mutants accumulated a pre-vacuolar endosome-like compartment. The mutant alleles causing the defects were identified as the members of the VPS4 gene locus, each harbouring single-point mutations leading to amino-acid exchanges at positions 233 (E233Q), 211 (E211 K), and 178 (G178D). These mutations all reside within a 200 amino-acid-long ATPase module, common to members of the AAA-protein family. The VPS4 gene product shows homology to the yeast Sec18p (50% similarity and 25% identity), which is involved in several vesicle-mediated protein transport steps and homotypic membrane fusion events. Disruption of the VPS4 gene leads to a recessive vacuolar protein-sorting phenotype. About 40% of newly synthesized CPY is secreted as the Golgi-modified p2CPY precursor form. Transport of secretory proteins to the plasma membrane is normal as demonstrated by the secretion of invertase and alpha-factor. The alpha-factor, however, is secreted as a partially processed precursor, caused by defects in late Golgi function. The vps4 mutants also exhibit defects in fluid-phase endocytosis, as demonstrated by the accumulation of Lucifer Yellow in a pre-vacuolar endosome-like compartment. Based on the pleiotropic phenotype of the vps4 mutants and on the sequence homology to NSF/Sec18p, we propose that the VPS4 gene product is required for efficient transport out of the pre-vacuolar endosome-like compartment.
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PMID:The VPS4 gene is involved in protein transport out of a yeast pre-vacuolar endosome-like compartment. 921 89

In the yeast Saccharomyces cerevisiae, autophagy, a bulk protein degradation in the vacuole, is induced in response to nutrient starvation. In a screen for mutations that result in induction of autophagy even in the presence of nutrients, we have isolated four mutants representing two csc complementation groups. These mutants induce autophagy of which activity is represented by activation of truncated alkaline phosphatase that is designed to be expressed in the cytosol. CSC1 was cloned by complementation of loss of viability phenotype of csc1-1 mutant and shown to be identical to END13/VPS4/GRD13. Though csc1-1 mutation is recessive, cells of delta csc1 do not induce autophagy in rich media, suggesting that csc1-1 allele is not a complete loss-of-function. Csc1p is a member of novel ATPase family named AAA protein including Sec18p/NSF, Cdc48p/p97, and Pas8p. Mutation site in csc1-1 is found in the SRH region that is highly conserved among AAA proteins. Cells of csc1-1 show sorting defect of CPY and the appearance of the class E compartment. These mutant phenotypes suggest the role of the protein that is involved in the traffic among the Golgi, endosome, and the vacuole in autophagy.
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PMID:Mutational analysis of Csc1/Vps4p: involvement of endosome in regulation of autophagy in yeast. 943 54

Vps4p is an AAA-type ATPase required for efficient transport of biosynthetic and endocytic cargo from an endosome to the lysosome-like vacuole of Saccharomyces cerevisiae. Vps4p mutants that do not bind ATP or are defective in ATP hydrolysis were characterized both in vivo and in vitro. The nucleotide-free or ADP-bound form of Vps4p existed as a dimer, whereas in the ATP-locked state, Vps4p dimers assembled into a decameric complex. This suggests that ATP hydrolysis drives a cycle of association and dissociation of Vps4p dimers/decamers. Nucleotide binding also regulated the association of Vps4p with an endosomal compartment in vivo. This membrane association required the N-terminal coiled-coil motif of Vps4p, but deletion of the coiled-coil domain did not affect ATPase activity or oligomeric assembly of the protein. Membrane association of two previously uncharacterized class E Vps proteins, Vps24p and Vps32p/Snf7p, was also affected by mutations in VPS4. Upon inactivation of a temperature-conditional vps4 mutant, Vps24p and Vps32p/Snf7p rapidly accumulated in a large membrane-bound complex. Immunofluorescence indicated that both proteins function with Vps4p at a common endosomal compartment. Together, the data suggest that the Vps4 ATPase catalyzes the release (uncoating) of an endosomal membrane-associated class E protein complex(es) required for normal morphology and sorting activity of the endosome.
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PMID:The Vps4p AAA ATPase regulates membrane association of a Vps protein complex required for normal endosome function. 960 81

end13-1 was isolated in a screen for endocytosis mutants and has been shown to have a post-internalisation defect in endocytic transport as well as a defect in vacuolar protein sorting (Vps(-) phenotype), leading to secretion of newly synthesised vacuolar proteins. Here we demonstrate that END13 is identical to VPS4, encoding an AAA (ATPase associated with a variety of cellular activities)-family ATPase. We also report that the end13-1 mutation is a serine 335 to phenylalanine substitution in the AAA-ATPase domain of End13p/Vps4p. It has been reported that mutant cells lacking End13p/Vps4p (end13(vps4)Delta) accumulate endocytosed marker dyes, plasma membrane receptors and newly synthesised vacuolar hydrolase precursors in an endosomal compartment adjacent to the vacuole (prevacuolar compartment, or PVC). We find, however, that the end13 mutants have defects in transport of endocytosed fluorescent dyes, plasma membrane receptors and ligands from small peripherally located early endosomes to larger late endosomes, which are often located adjacent to the vacuole. Our results indicate that End13p/Vps4p may play an important role in multiple steps of membrane traffic through the endocytic pathway.
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PMID:End13p/Vps4p is required for efficient transport from early to late endosomes in Saccharomyces cerevisiae. 1132 80

The yeast Vps4 protein (Vps4p) is a member of the AAA protein family (ATPases associated with diverse cellular activities) and a key player in the transport of proteins out of a prevacuolar endosomal compartment. In human cells, we identified two non-allelic orthologous proteins (VPS4-A and VPS4-B) of yeast Vps4p. The human VPS4-A and VPS4-B proteins display a high degree of sequence identity to each other (80 %) and to the yeast Vps4 protein (59 and 60 %, respectively). Yeast cells lacking a functional VPS4 gene exhibit a temperature-sensitive growth defect and mislocalise a carboxypeptidase Y-invertase fusion protein to the cell surface. Heterologous expression of human VPS4 genes in vps4 mutant yeast strains led, in the case of human VPS4-A, to a partial and, in the case of human VPS4-B, to a complete suppression of the temperature-sensitive growth defect. The vacuolar protein sorting defect of vps4 mutant yeast cells was complemented completely by heterologous expressed human VPS4-B protein, and partially by the human VPS4-A protein. Expression of mutant human VPS4-A (E228Q) and VPS4-B (E235Q) proteins, harbouring single amino acid exchanges in their AAA domains, induced dominant-negative vacuolar protein sorting defects in wild-type yeast cells in both cases. Two-hybrid experiments suggest that the human VPS4-A and VPS4-B proteins can form heteromeric complexes, and subcellular localisation experiments indicate that both human VPS4 proteins associate with endosomal compartments in yeast. Based on these results, we conclude that both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step, similar to the Vps4p in yeast.
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PMID:Mammalian cells express two VPS4 proteins both of which are involved in intracellular protein trafficking. 1156 10

The VPS4 gene is a member of the AAA-family; it codes for an ATPase which is involved in lysosomal/endosomal membrane trafficking. VPS4 genes are present in virtually all eukaryotes. Exhaustive data mining of all available genomic databases from completely or partially sequenced organisms revealed the existence of up to three paralogues, VPS4a, -b, and -c. Whereas in the genome of lower eukaryotes like yeast only one VPS4 representative is present, we found that mammals harbour two paralogues, VPS4a and VPS4b. Most interestingly, the Fugu fish contains a third VPS4 paralogue (VPS4c). Sequence comparison of the three VPS4 paralogues indicates that the Fugu VPS4c displays sequence features intermediate between VPS4a and VPS4b. Using complete mammalian VPS4a and VPS4b cDNA clones as probes, genomic clones of both VPS4 paralogues in human and mouse were identified and sequenced. The chromosomal loci of all four VPS4 genes were determined by independent methods. A BLAST search of the human genome database with the human VPS4A sequence yielded a double match, most likely due to a faulty assembly of sequence contigs in the human draft sequence. Fluorescent in situ hybridization and radiation hybrid analyses demonstrated that human and mouse VPS4A/a and VPS4B/b are located on syntenic chromosomal regions. Northern blot and semi-quantitative reverse transcription analyses showed that mouse VPS4a and VPS4b are differentially expressed in different organs, suggesting that the two paralogues have developed different functional properties since their divergence. To investigate the subcellular distribution of the murine VPS4 paralogues, we transiently expressed various fluorescent VPS4 fusion proteins in mouse 3T3 cells. All tested VPS4 fusion proteins were found in the cytosol. Expression of dominant-negative mutant VPS4 fusion proteins led to their concentration in the perinuclear region. Co-expression of VPS4a-GFP and VPS4b-dsRed fusion proteins revealed a partial co-localization that was most prominent with mutant VPS4a and VPS4b proteins. A physical interaction between the mouse paralogues was also supported by two-hybrid analyses.
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PMID:Comparative sequence and expression analyses of four mammalian VPS4 genes. 1259 41

The yeast genome encodes seven oxysterol binding protein homologs, Osh1p-Osh7p, which have been implicated in regulating intracellular lipid and vesicular transport. Here, we show that both Osh6p and Osh7p interact with Vps4p, a member of the AAA (ATPases associated with a variety of cellular activities) family. The coiled-coil domain of Osh7p was found to interact with Vps4p in a yeast two-hybrid screen and the interaction between Osh7p and Vps4p appears to be regulated by ergosterol. Deletion of VPS4 induced a dramatic increase in the membrane-associated pools of Osh6p and Osh7p and also caused a decrease in sterol esterification, which was suppressed by overexpression of OSH7. Lastly, overexpression of the coiled-coil domain of Osh7p (Osh7pCC) resulted in a multivesicular body sorting defect, suggesting a dominant negative role of Osh7pCC possibly through inhibiting Vps4p function. Our data suggest that a common mechanism may exist for AAA proteins to regulate the membrane association of yeast OSBP proteins and that these two protein families may function together to control subcellular lipid transport.
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PMID:AAA ATPases regulate membrane association of yeast oxysterol binding proteins and sterol metabolism. 1609 48

The VPS4 AAA ATPases function both in endosomal vesicle formation and in the budding of many enveloped RNA viruses, including HIV-1. VPS4 proteins act by binding and catalyzing release of the membrane-associated ESCRT-III protein lattice, thereby allowing multiple rounds of protein sorting and vesicle formation. Here, we report the solution structure of the N-terminal VPS4A microtubule interacting and transport (MIT) domain and demonstrate that the VPS4A MIT domain binds the C-terminal half of the ESCRT-III protein, CHMP1B (Kd = 20 +/- 13 microM). The MIT domain forms an asymmetric three-helix bundle that resembles the first three helices in a tetratricopeptide repeat (TPR) motif. Unusual interhelical interactions are mediated by a series of conserved aromatic residues that form coiled-coil interactions between the second two helices and also pack against the conserved alanines that interdigitate between the first two helices. Mutational analyses revealed that a conserved leucine residue (Leu-64) on the third helix that would normally bind the fourth helix in an extended TPR is used to bind CHMP1B, raising the possibility that ESCRT-III proteins may bind by completing the TPR motif.
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PMID:Structure and ESCRT-III protein interactions of the MIT domain of human VPS4A. 1617 32

VPS4 ATPases function in multivesicular body formation and in HIV-1 budding. Here, we report the crystal structure of monomeric apo human VPS4B/SKD1 (hVPS4B), which is composed of five distinct elements: a poorly ordered N-terminal MIT domain that binds ESCRT-III substrates, large (mixed alpha/beta) and small (alpha) AAA ATPase domains that closely resemble analogous domains in the p97 D1 ATPase cassette, a three-stranded antiparallel beta domain inserted within the small ATPase domain, and a novel C-terminal helix. Apo hVPS4B and yeast Vps4p (yVps4p) proteins dimerized in solution, and assembled into larger complexes (10-12 subunits) upon ATP binding. Human and yeast adaptor proteins (LIP5 and yVta1p, respectively) bound the beta domains of the fully assembled hVPS4B and yVps4p proteins. We therefore propose that Vps4 proteins cycle between soluble, inactive low molecular weight complexes and active, membrane-associated double-ring structures that bind ATP and coassemble with LIP5/Vta1. Finally, HIV-1 budding was inhibited by mutations in a loop that projects into the center of the modeled hVPS4B rings, suggesting that hVPS4B may release the assembled ESCRT machinery by pulling ESCRT-III substrates up into the central pore.
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PMID:Structural and mechanistic studies of VPS4 proteins. 1619 69


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