Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0271742 (AAA)
 3,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mouse SKD1 protein displays a high degree of sequence identity (62%) to the yeast Vps4 protein, which is involved in the transport of proteins out of a prevacuolar/endosomal compartment. We isolated the mouse SKD1 locus and found that the SKD1 gene is split into 11 exons covering a region of 29kb of the genome. Interestingly, the exon/intron structure reflects to a certain degree the proposed domain structure of the protein, since the 5' located coiled-coil region and the AAA domain are flanked by introns. Analysis of the promoter region, which revealed features common for 'housekeeping genes', is consistent with previous results of a mouse multi-tissue Northern blot, confirming that SKD1 is a ubiquitously expressed gene. Expression of the full-length SKD1 cDNA in a vps4 disrupted yeast strain suppressed the temperature-sensitive growth defect of the vps4 mutant strain. Overexpression of wild type and expression of mutant Vps4 and SKD1 proteins, harbouring single amino acid exchanges in their AAA domains, induced a dominant-negative vacuolar protein sorting defect in wild type yeast cells, indicating that mouse SKD1 protein and yeast Vps4p fulfil similar functions.
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PMID:Cloning, characterisation, and functional expression of the Mus musculus SKD1 gene in yeast demonstrates that the mouse SKD1 and the yeast VPS4 genes are orthologues and involved in intracellular protein trafficking. 1039 49

The mouse SKD1 is an AAA-type ATPase homologous to the yeast Vps4p implicated in transport from endosomes to the vacuole. To elucidate a possible role of SKD1 in mammalian endocytosis, we generated a mutant SKD1, harboring a mutation (E235Q) that is equivalent to the dominant negative mutation (E233Q) in Vps4p. Overexpression of the mutant SKD1 in cultured mammalian cells caused defect in uptake of transferrin and low-density lipoprotein. This was due to loss of their receptors from the cell surface. The decrease of the surface transferrin receptor (TfR) was correlated with expression levels of the mutant protein. The mutant protein displayed a perinuclear punctate distribution in contrast to a diffuse pattern of the wild-type SKD1. TfR, the lysosomal protein lamp-1, endocytosed dextran, and epidermal growth factor but not markers for the secretory pathway were accumulated in the mutant SKD1-localized compartments. Degradation of epidermal growth factor was inhibited. Electron microscopy revealed that the compartments were exaggerated multivesicular vacuoles with numerous tubulo-vesicular extensions containing TfR and endocytosed horseradish peroxidase. The early endosome antigen EEA1 was also redistributed to these aberrant membranes. Taken together, our findings suggest that SKD1 regulates morphology of endosomes and membrane traffic through them.
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PMID:The mouse SKD1, a homologue of yeast Vps4p, is required for normal endosomal trafficking and morphology in mammalian cells. 1067 28

Mouse SKD1 AAA ATPase is involved in the sorting and transport from endosomes; cells overexpressing a dominant-negative mutant, SKD1(E235Q) were defective in endosomal transport to both the plasma membranes and lysosomes (Yoshimori et al., 2000). In the present study, we demonstrated that overexpression of SKD1(E235Q) using an adenovirus delivery system caused a defect in autophagy-dependent bulk protein degradation. Morphological observations suggested that this inhibition of autophagy results from an impairment of autolysosome formation. SKD1(E235Q) overexpression also inhibited transport from endosomes to autophagosomes, an event normally occurring prior to fusion with lysosomes. These results indicate that SKD1-dependent endosomal membrane trafficking is required for formation of autolysosomes.
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PMID:SKD1 AAA ATPase-dependent endosomal transport is involved in autolysosome formation. 1193 16

The mammalian phosphatidylinositol (PtdIns)- 5-P/PtdIns-3,5-P(2)-producing kinase PIKfyve and AAA ATPase SKD1, as their yeast counterparts, are implicated in the formation and function of multivesicular bodies/late endosomes. Point mutations inhibiting the enzyme activities convert PIKfyve and SKD1 into dominant-negative mutants (PIKfyve(K1831E) and SKD1(E235Q)), whose expression in cells of kidney origin induces a vacuolation phenotype. This phenotype closely resembles the changes in late endosomal-lysosomal morphology that occur following cell exposure to the vacuolating cytotoxin (VacA) from Helicobacter pylori. Here we have examined the possible functional relationship between PIKfyve and SKD1 as well as the role of these enzymes in the molecular mechanism of VacA-induced intracellular vacuolation. When co-expressed in COS cells, PIKfyve(WT) reduced SKD1(E235Q)dependent vacuole formation, whereas SKD1(WT) did not alter the vacuolation induced by PIKfyve(K1831E). In addition, SKD1(E235Q) disrupted the normal distribution of PIKfyve(WT). Expression of PIKfyve(WT) in COS and HEK293 cells inhibited vacuolation induced by subsequent intoxication with VacA, and microinjection of the PIKfyve lipid product PtdIns-3,5-P(2) produced a similar inhibitory effect. In contrast, in COS cells expressing SKD1(WT), VacA induced the formation of characteristic vacuoles with an efficiency similar to that in the control cells. These observations demonstrate that, although PIKfyve and SKD1 are functionally related, only PIKfyve regulates VacA action, and suggest that the inhibition of PIKfyve PtdIns-3,5-P(2)-producing activity is a key molecular event in VacA-induced cellular vacuolation.
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PMID:PIKfyve Kinase and SKD1 AAA ATPase define distinct endocytic compartments. Only PIKfyve expression inhibits the cell-vacoulating activity of Helicobacter pylori VacA toxin. 1221 28

Alix (ALG-2-interacting protein X) is a 95-kDa protein that interacts with an EF-hand type Ca(2+)-binding protein, ALG-2 (apoptosis-linked gene 2), through its C-terminal proline-rich region. In this study, we searched for proteins that interact with human AlixDeltaC (a truncated form not containing the C-terminal region) by using a yeast two-hybrid screen, and we identified two similar human proteins, CHMP4a and CHMP4b (chromatin-modifying protein; charged multivesicular body protein), as novel binding partners of Alix. The interaction of Alix with CHMP4b was confirmed by a glutathione S-transferase pull-down assay and by co-immunoprecipitation experiments. Fluorescence microscopic analysis revealed that CHMP4b transiently expressed in HeLa cells mainly exhibited a punctate distribution in the perinuclear area and co-localized with co-expressed Alix. The distribution of CHMP4b partly overlapped the distributions of early and late endosomal marker proteins, EEA1 (early endosome antigen 1) and Lamp-1 (lysosomal membrane protein-1), respectively. Transient overexpression of CHMP4b induced the accumulation of ubiquitinated proteins as punctate patterns that were partly overlapped with the distribution of CHMP4b and inhibited the disappearance of endocytosed epidermal growth factor. In contrast, stably expressed CHMP4b in HEK293 cells was observed diffusely in the cytoplasm. Transient overexpression of AlixDeltaC in stably CHMP4b-expressing cells, however, induced formation of vesicle-like structures in which CHMP4b and AlixDeltaC were co-localized. SKD1(E235Q), a dominant negative form of the AAA type ATPase SKD1 that plays critical roles in the endocytic pathway, was co-immunoprecipitated with CHMP4b. Furthermore, CHMP4b co-localized with SKD1(E235Q) as punctate patterns in the perinuclear area, and Alix was induced to exhibit dot-like distributions overlapped with SKD1(E235Q) in HeLa cells. These results suggest that CHMP4b and Alix participate in formation of multivesicular bodies by cooperating with SKD1.
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PMID:The ALG-2-interacting protein Alix associates with CHMP4b, a human homologue of yeast Snf7 that is involved in multivesicular body sorting. 1286 Sep 94

SKD1 belongs to the AAA-ATPase family and is one of the mammalian class E Vps (vacuolar protein sorting) proteins. Previously we have reported that the overexpression of an ATPase activity-deficient form of SKD1 (suppressor of potassium transport growth defect), SKD1(E235Q), leads the perturbation of membrane transport through endosomes and lysosomes, however, the molecular mechanism behind the action of SKD1 is poorly understood. We have identified two SKD1-binding proteins, SBP1 and mVps2, by yeast two-hybrid screening and we assign them as mammalian class E Vps proteins. The primary sequence of SBP1 indicates 22.5% identity with that of Vta1p from Saccharomyces cerevisiae, which was recently identified as a novel class E Vps protein binding to Vps4p. In fact, SBP1 binds directly to SKD1 through its C-terminal region (198-309). Endogenous SBP1 is exclusively localized to cytosol, however it is redirected to an aberrant endosomal structure, the E235Q compartment, in the cells expressing SKD1(E235Q). The ATPase activity of SKD1 regulates both the membrane association of, and assembly of, a large hetero-oligomer protein complex, containing SBP1, which is potentially involved in membrane transport through endosomes and lysosomes. The N-terminal half (1-157) of human SBP1 is identical to lyst-interacting protein 5 and intriguingly, SKD1 ATPase activity significantly influences the membrane association of lyst protein. The SKD1-SBP1 complex, together with lyst protein, may function in endosomal membrane transport. A primary sequence of mVps2, a mouse homologue of human CHMP2A/BC-2, indicates 44.4% identity with Vps2p/Did4p/Chm2p from Saccharomyces cerevisiae. mVps2 also interacts with SKD1 and is localized to the E235Q compartment. Intriguingly, the N-terminal coiled-coil region of mVps2 is required for the formation of the E235Q compartment but not for binding to SKD1. We propose that both SBP1 and mVps2 regulate SKD1 function in mammalian cells.
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PMID:Mammalian class E Vps proteins, SBP1 and mVps2/CHMP2A, interact with and regulate the function of an AAA-ATPase SKD1/Vps4B. 1517 23

A full-length salt-induced transcript homologous to SKD1 (suppressor of K(+) transport growth defect) of the AAA (ATPase associated with a variety of cellular activities)-type ATPase family has been identified from the halophyte Mesembryanthemum crystallinum (ice plant). The expression of mcSKD1 was induced by 200 mM NaCl or higher in cultured ice plant cells. When cultured ice plant cells were grown in a high K(+) (42.6 mM) medium, the level of mcSKD1 expression decreased. At the whole plant level, constitutive expression of mcSKD1 was observed in roots, stems, leaves and floral organs. Addition of 400 mM NaCl increased the transcript level in roots and stems. The expression of atSKD1 , a homologue gene in Arabidopsis , was down regulated by salt stress. Under salt stress, mcSKD1 was preferentially expressed in the outer cortex of roots and stems and in the epidermal bladder cells of leaves. The mcSKD1 transcript was constitutively expressed in placenta and integuments of the developing floral buds. Expression of the full-length or C-terminal deletion of mcSKD1 was able to complement the K(+) uptake-defect phenotype in mutant Saccharomyces cerevisiae , which is defective in high- and low-affinity K(+) uptake. Deletion of the N-terminal coiled-coil motif of mcSKD1, a structure required for membrane association, resulted in greatly reduced K(+) transport. Expression of mcSKD1 also increased the salt-tolerant ability of yeast mutants and either N- or C-terminal deletion decreased the efficiency. The physiological relevancies of mcSKD1 for K(+) uptake under high salinity environments are discussed.
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PMID:Tissue-specific expression and functional complementation of a yeast potassium-uptake mutant by a salt-induced ice plant gene mcSKD1. 1560 58

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

The autophagic process was first described in mammalian cells several decades ago. After their formation as double-membraned vacuoles containing cytoplasmic material, autophagic vacuoles or autophagosomes undergo a stepwise maturation including fusion with both endosomal and lysosomal vesicles. However, the molecular mechanisms regulating these fusion steps have begun to emerge only recently. The list of newly discovered molecules that regulate the maturation of autophagosomes to degradative autolysosomes includes the AAA ATPase SKD1, the small GTP binding protein Rab7, and possibly also the Alzheimer-linked presenilin 1. This review combines previous data on the endo/lysosomal fusion steps during autophagic vacuole maturation with recent findings on the molecules regulating these fusion steps. Interestingly, autophagic vacuole maturation appears to be blocked in certain human diseases including neuronal ceroid lipofuscinosis and Danon disease. This suggests that autophagy has important housekeeping or protective functions because a block in autophagic maturation causes a disease.
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PMID:Maturation of autophagic vacuoles in Mammalian cells. 1687 26

In yeast and mammals, the AAA ATPase Vps4p/SKD1 (for Vacuolar protein sorting 4/SUPPRESSOR OF K(+) TRANSPORT GROWTH DEFECT1) is required for the endosomal sorting of secretory and endocytic cargo. We identified a VPS4/SKD1 homolog in Arabidopsis thaliana, which localizes to the cytoplasm and to multivesicular endosomes. In addition, green fluorescent protein-SKD1 colocalizes on multivesicular bodies with fluorescent fusion protein endosomal Rab GTPases, such as ARA6/RabF1, RHA1/RabF2a, and ARA7/RabF2b, and with the endocytic marker FM4-64. The expression of SKD1(E232Q), an ATPase-deficient version of SKD1, induces alterations in the endosomal system of tobacco (Nicotiana tabacum) Bright Yellow 2 cells and ultimately leads to cell death. The inducible expression of SKD1(E232Q) in Arabidopsis resulted in enlarged endosomes with a reduced number of internal vesicles. In a yeast two-hybrid screen using Arabidopsis SKD1 as bait, we isolated a putative homolog of mammalian LYST-INTERACTING PROTEIN5 (LIP5)/SKD1 BINDING PROTEIN1 and yeast Vta1p (for Vps twenty associated 1 protein). Arabidopsis LIP5 acts as a positive regulator of SKD1 by increasing fourfold to fivefold its in vitro ATPase activity. We isolated a knockout homozygous Arabidopsis mutant line with a T-DNA insertion in LIP5. lip5 plants are viable and show no phenotypic alterations under normal growth conditions, suggesting that basal SKD1 ATPase activity is sufficient for plant development and growth.
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PMID:The Arabidopsis AAA ATPase SKD1 is involved in multivesicular endosome function and interacts with its positive regulator LYST-INTERACTING PROTEIN5. 1746 62


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