Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The yeast AAA-ATPase Cdc48 and the ubiquitin fusion degradation (UFD) proteins play important, evolutionarily conserved roles in ubiquitin dependent protein degradation. The N-terminal domain of Cdc48 interacts with substrate-recruiting cofactors, whereas the C terminus of Cdc48 binds to proteins such as Ufd3 that process substrates. Ufd3 is essential for efficient protein degradation and for maintaining cellular ubiquitin levels. This protein contains an N-terminal WD40 domain, a central ubiquitin-binding domain, and a C-terminal Cdc48-binding PUL domain. The crystal structure of the PUL domain reveals an Armadillo repeat with high structural similarity to importin-alpha, and the Cdc48-binding site could be mapped to the concave surface of the PUL domain by biochemical studies. Alterations of the Cdc48 binding site of Ufd3 by site-directed mutagenesis resulted in a depletion of cellular ubiquitin pools and reduced activity of the ubiquitin fusion degradation pathway. Therefore, our data provide direct evidence that the functions of Ufd3 in ubiquitin homeostasis and protein degradation depend on its interaction with the C terminus of Cdc48.
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PMID:An Armadillo motif in Ufd3 interacts with Cdc48 and is involved in ubiquitin homeostasis and protein degradation. 1980 80

PLAA (ortholog of yeast Doa1/Ufd3, also know as human PLAP or phospholipase A2-activating protein) has been implicated in a variety of disparate biological processes that involve the ubiquitin system. It is linked to the maintenance of ubiquitin levels, but the mechanism by which it accomplishes this is unclear. The C-terminal PUL (PLAP, Ufd3p, and Lub1p) domain of PLAA binds p97, an AAA ATPase, which among other functions helps transfer ubiquitinated proteins to the proteasome for degradation. In yeast, loss of Doa1 is suppressed by altering p97/Cdc48 function indicating that physical interaction between PLAA and p97 is functionally important. Although the overall regions of interaction between these proteins are known, the structural basis has been unavailable. We solved the high resolution crystal structure of the p97-PLAA complex showing that the PUL domain forms a 6-mer Armadillo-containing domain. Its N-terminal extension folds back onto the inner curvature forming a deep ridge that is positively charged with residues that are phylogenetically conserved. The C terminus of p97 binds in this ridge, where the side chain of p97-Tyr(805), implicated in phosphorylation-dependent regulation, is buried. Expressed in doa1Delta null cells, point mutants of the yeast ortholog Doa1 that disrupt this interaction display slightly reduced ubiquitin levels, but unlike doa1Delta null cells, showed only some of the growth phenotypes. These data suggest that the p97-PLAA interaction is important for a subset of PLAA-dependent biological processes and provides a framework to better understand the role of these complex molecules in the ubiquitin system.
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PMID:Structure and function of the PLAA/Ufd3-p97/Cdc48 complex. 1988 78

Switches between different phenotypes and their underlying states of gene transcription occur as cells respond to intrinsic developmental cues or adapt to changing environmental conditions. Post-translational modification of the master regulatory transcription factors that define the initial phenotype is a common strategy to direct such transitions. Emerging evidence indicates that the modification of key transcription factors by the small polypeptide ubiquitin has a central role in many of these transitions. However, the molecular mechanisms by which ubiquitylation regulates the switching of promoters between active and inactive states are largely unknown. Ubiquitylation of the yeast transcriptional repressor alpha2 is necessary to evoke the transition between mating-types, and here we dissect the impact of this modification on alpha2 dynamics at its target promoters. Ubiquitylation of alpha2 does not alter DNA occupancy by depleting the existing pool of the transcription factor, despite its well-characterized function in directing repressor turnover. Rather, alpha2 ubiquitylation has a direct role in the rapid removal of the repressor from its DNA targets. This disassembly of alpha2 from DNA depends on the ubiquitin-selective AAA-ATPase Cdc48. Our findings expand the functional targets of Cdc48 to include active transcriptional regulatory complexes in the nucleus. These data reveal an ubiquitin-dependent extraction pathway for dismantling transcription factor-DNA complexes and provide an archetype for the regulation of transcriptional switching events by ubiquitylation.
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PMID:A ubiquitin-selective AAA-ATPase mediates transcriptional switching by remodelling a repressor-promoter DNA complex. 1991 56

During cell division, chromosomes condense so that the replicated chromatids can be segregated by the mitotic spindle. While condensation is governed by cyclin-dependent kinase 1 (Cdk1) during mitotic entry and early mitosis, it is still poorly understood how condensation is maintained during anaphase after Cdk1 inactivation, and how decondensation is triggered in telophase. Here, we review recent reports that point to a novel role of Aurora B kinase in maintaining condensation and preventing premature nuclear envelope formation during exit from mitosis. Timely decondensation and nuclear envelope formation at the end of mitosis may then be triggered by two mechanisms. One is removing Aurora B phosphorylation marks from chromatin by specific phosphatases. The other is removing and inactivating Aurora B kinase itself by the ubiquitin system. We have recently provided evidence that the AAA ATPase Cdc48/p97 plays a central role in the inactivation of Aurora B, as it extracts ubiquitinated Aurora B from chromosomes and thus reduces chromatinassociated Aurora B activity.
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PMID:A role for Cdc48/p97 and Aurora B in controlling chromatin condensation during exit from mitosis. 2013 Jun 76

Cdc48p/p97 is a highly conserved essential AAA protein that is required for many cellular processes, and is identified as a causative gene for an autosomal dominant human disorder, inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD). Cdc48p/p97 is composed of an N-terminal domain, followed by two AAA domains (D1 and D2) whose ATPase activities have been characterized extensively. In this study, effects of mutations on the essential functions of yeast Cdc48p/p97 in vivo were systematically analyzed. IBMPFD-related mutations do not affect the essential functions of Cdc48p/p97. Loss of ATPase activity of D2 leads to loss of function of the protein in vivo. In contrast, ATPase activity of D1 per se is not essential, but a mutation locking D1 in an ATP-bound form is exceptionally lethal. Site-directed and random mutagenesis analyses suggest that the ATP-bound form of D1 changes an inter-domain interaction, thereby perturbing an essential function of Cdc48p/p97.
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PMID:ATP-bound form of the D1 AAA domain inhibits an essential function of Cdc48p/p97. 2013 Jun 84

The assembly, disassembly and dynamic movement of macromolecules are integral to cell physiology. The ubiquitin-selective chaperone Cdc48 (p97 in Metazoa), an AAA-ATPase, might facilitate such processes in the cell cycle. Cdc48 in budding yeast was initially isolated from a mitotic mutant. However, its function in mitosis remained elusive. Here we show that the temperature-sensitive cdc48-3 mutant and depletion of cofactor Shp1 (p47 in Metazoa) cause cell-cycle arrest at metaphase. The arrest is due to a defect in bipolar attachment of the kinetochore that activates the spindle checkpoint. Furthermore, Cdc48-Shp1 positively regulates Glc7/protein phosphatase 1 by facilitating nuclear localization of Glc7, whereas it opposes Ipl1/Aurora B kinase activity. Thus, we propose that Cdc48-Shp1 promotes nuclear accumulation of Glc7 to counteract Ipl1 activity. Our results identify Cdc48 and Shp1 as critical components that balance the kinase and phosphatase activities at the kinetochore in order to achieve stable bipolar attachment.
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PMID:The AAA-ATPase Cdc48 and cofactor Shp1 promote chromosome bi-orientation by balancing Aurora B activity. 2048 56

Mutations in p97, a major cytosolic AAA (ATPases associated with a variety of cellular activities) chaperone, cause inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD). IBMPFD mutants have single amino-acid substitutions at the interface between the N-terminal domain (N-domain) and the adjacent AAA domain (D1), resulting in a reduced affinity for ADP. The structures of p97 N-D1 fragments bearing IBMPFD mutations adopt an atypical N-domain conformation in the presence of Mg(2+).ATPgammaS, which is reversible by ADP, showing for the first time the nucleotide-dependent conformational change of the N-domain. The transition from the ADP- to the ATPgammaS-bound state is accompanied by a loop-to-helix conversion in the N-D1 linker and by an apparent re-ordering in the N-terminal region of p97. X-ray scattering experiments suggest that wild-type p97 subunits undergo a similar nucleotide-dependent N-domain conformational change. We propose that IBMPFD mutations alter the timing of the transition between nucleotide states by destabilizing the ADP-bound form and consequently interfere with the interactions between the N-domains and their substrates.
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PMID:A novel ATP-dependent conformation in p97 N-D1 fragment revealed by crystal structures of disease-related mutants. 2051 13

Proteins imported into the endoplasmic reticulum (ER) are scanned for their folding status. Those that do not reach their native conformation are degraded via the ubiquitin-proteasome system. This process is called ER-associated degradation (ERAD). Der1 is known to be one of the components required for efficient degradation of soluble ERAD substrates like CPY(*) (mutated carboxypeptidase yscY). A homologue of Der1 exists, named Dfm1. No function of Dfm1 has been discovered, although a C-terminally hemagglutinin (HA)(3)-tagged Dfm1 protein has been shown to interact with the ERAD machinery. In our studies, we found Dfm1-HA(3) to be an ERAD substrate and therefore not suitable for functional studies of Dfm1 in ERAD. We found cellular, non-tagged Dfm1 to be a stable protein. We identified Dfm1 to be part of complexes which contain the ERAD-L ligase Hrd1/Der3 and Der1 as well as the ERAD-C ligase Doa10. In addition, ERAD of Ste6(*)-HA(3) was strongly dependent on Dfm1. Interestingly, Dfm1 forms a complex with the AAA-ATPase Cdc48 in a strain lacking the Cdc48 membrane-recruiting component Ubx2. This complex does not contain the ubiquitin ligases Hrd1/Der3 and Doa10. The existence of such a complex might point to an additional function of Dfm1 independent from ERAD.
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PMID:Dfm1 forms distinct complexes with Cdc48 and the ER ubiquitin ligases and is required for ERAD. 2057 15

The molecular details of the biogenesis of double-membraned autophagosomes are poorly understood. We identify the Saccharomyces cerevisiae AAA-adenosine triphosphatase Cdc48 and its substrate-recruiting cofactor Shp1/Ubx1 as novel components needed for autophagosome biogenesis. In mammals, the Cdc48 homologue p97/VCP and the Shp1 homologue p47 mediate Golgi reassembly by extracting an unknown monoubiquitinated fusion regulator from a complex. We find no requirement of ubiquitination or the proteasome system for autophagosome biogenesis but detect interaction of Shp1 with the ubiquitin-fold autophagy protein Atg8. Atg8 coupled to phosphatidylethanolamine (PE) is crucial for autophagosome elongation and, in vitro, mediates tethering and hemifusion. Interaction with Shp1 requires an FK motif within the N-terminal non-ubiquitin-like Atg8 domain. Based on our data, we speculate that autophagosome formation, in contrast to Golgi reassembly, requires a complex in which Atg8 functionally substitutes ubiquitin. This, for the first time, would give a rationale for use of the ubiquitin-like Atg8 during macroautophagy and would explain why Atg8-PE delipidation is necessary for efficient macroautophagy.
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PMID:Cdc48/p97 and Shp1/p47 regulate autophagosome biogenesis in concert with ubiquitin-like Atg8. 2085 2

Macroautophagy sequesters superflous cytosol and organelles into double-membraned autophagosomes. Over 30 autophagy-related (ATG) genes have been identified without elucidating the molecular details of autophagosome biogenesis. All proposed models for autophagosome formation require membrane fusion events (Fig. 1). Previous studies assumed that the autophagic machinery mediates these membrane fusions in a SNARE-independent manner and identified the ubiquitin-like protein Atg8 as a key component especially for elongation of the forming autophagosome. However, if and how Atg8 mediates membrane fusion and why a ubiquitin-like protein is needed for autophagosome biogenesis remained open questions. Since nuclear envelope growth and fusion of Golgi fragments are topologically similar to autophagosome formation and depend on the AAA (+) ATPase p97/VCP and p47 we analyzed the involvement of their yeast homologues Cdc48 and Shp1 in macroautophagy.
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PMID:Cheating on ubiquitin with Atg8. 2115 Mar 10


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