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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 roles of two adjacent genes in the Staphylococcus aureus chromosome with functions in starvation survival and the response to stressful conditions have been characterized. One of these, hprT, encoding a hypoxanthine-guanine phosphoribosyltransferase homologue, was initially identified in a transposon mutagenesis screen. Mutation of hprT affects starvation survival in amino-acid-limiting conditions and the ability of S. aureus to grow in high-salt concentrations. Downstream of hprT is ftsH, which encodes a membrane-bound, ATP- and Zn(2+)-dependent 'AAA'-type protease. Mutation of ftsH in S. aureus leads to pleiotropic defects including slower growth, sensitivity to salt, acid, methyl viologen and potassium tellurite stresses, and reduced survival in amino-acid- or phosphate-limiting conditions. Both hprT-lacZ and ftsH-lacZ gene fusions are expressed maximally in the post-exponential phase of growth. Although secretion of exoproteins is not affected, an ftsH mutant is attenuated in a murine skin lesion model of pathogenicity.
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PMID:Role of the hprT-ftsH locus in Staphylococcus aureus. 1476 15

AAA ATPases form a large protein family with manifold cellular roles. They belong to the AAA+ superfamily of ringshaped P-loop NTPases, which exert their activity through the energy-dependent unfolding of macromolecules. Phylogenetic analyses have suggested the existence of five major clades of AAA domains (proteasome subunits, metalloproteases, domains D1 and D2 of ATPases with two AAA domains, and the MSP1/katanin/spastin group), as well as a number of deeply branching minor clades. These analyses however have been characterized by a lack of consistency in defining the boundaries of the AAA family. We have used cluster analysis to delineate unambiguously the group of AAA sequences within the AAA+ superfamily. Phylogenetic and cluster analysis of this sequence set revealed the existence of a sixth major AAA clade, comprising the mitochondrial, membrane-bound protein BCS1 and its homologues. In addition, we identified several deep branches consisting mainly of hypothetical proteins resulting from genomic projects. Analysis of the AAA N-domains provided direct support for the obtained phylogeny for most branches, but revealed some deep splits that had not been apparent from phylogenetic analysis and some unexpected similarities between distant clades. It also revealed highly degenerate D1 domains in plant MSP1 sequences and in at least one deeply branching group of hypothetical proteins (YC46), showing that AAA proteins with two ATPase domains arose at least three times independently.
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PMID:Phylogenetic analysis of AAA proteins. 1503 33

AAA proteases are membrane-bound ATP-dependent proteases that are present in eubacteria, mitochondria and chloroplasts and that can degrade membrane proteins. Recent evidence suggests dislocation of membrane-embedded substrates for proteolysis to occur in a hydrophilic environment; however, next to nothing is known about the mechanism of this process. Here, we have analysed the role of the membrane-spanning domains of Yta10 and Yta12, which are conserved subunits of the hetero-oligomeric m-AAA protease in the mitochondria of Saccharomyces cerevisiae. We demonstrate that the m-AAA protease retains proteolytic activity after deletion of the transmembrane segments of either Yta10 or Yta12. Although the mutant m-AAA protease is still capable of processing cytochrome c peroxidase and degrading a peripheral membrane protein, proteolysis of integral membrane proteins is impaired. We therefore propose that transmembrane segments of m-AAA protease subunits have a direct role in the dislocation of membrane-embedded substrates.
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PMID:Membrane protein turnover by the m-AAA protease in mitochondria depends on the transmembrane domains of its subunits. 1520 78

FtsH is a cytoplasmic membrane protein that has N-terminally located transmembrane segments and a main cytosolic region consisting of AAA-ATPase and Zn2+-metalloprotease domains. It forms a homo-hexamer, which is further complexed with an oligomer of the membrane-bound modulating factor HflKC. FtsH degrades a set of short-lived proteins, enabling cellular regulation at the level of protein stability. FtsH also degrades some misassembled membrane proteins, contributing to their quality maintenance. It is an energy-utilizing and processive endopeptidase with a special ability to dislocate membrane protein substrates out of the membrane, for which its own membrane-embedded nature is essential. We discuss structure-function relationships of this intriguing enzyme, including the way it recognizes the soluble and membrane-integrated substrates differentially, on the basis of the solved structure of the ATPase domain as well as extensive biochemical and genetic information accumulated in the past decade on this enzyme.
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PMID:Cellular functions, mechanism of action, and regulation of FtsH protease. 1591 Feb 74

Endoplasmic reticulum (ER)-associated protein degradation requires the dislocation of selected substrates from the ER to the cytosol for proteolysis via the ubiquitin-proteasome system. The AAA ATPase Cdc48 (known as p97 or VCP in mammals) has a crucial, but poorly understood role in this transport step. Here, we show that Ubx2 (Sel1) mediates interaction of the Cdc48 complex with the ER membrane-bound ubiquitin ligases Hrd1 (Der3) and Doa10. The membrane protein Ubx2 contains a UBX domain that interacts with Cdc48 and an additional UBA domain. Absence of Ubx2 abrogates breakdown of ER proteins but also that of a cytosolic protein, which is ubiquitinated by Doa10. Intriguingly, our results suggest that recruitment of Cdc48 by Ubx2 is essential for turnover of both ER and non-ER substrates, whereas the UBA domain of Ubx2 is specifically required for ER proteins only. Thus, a complex comprising the AAA ATPase, a ubiquitin ligase and the recruitment factor Ubx2 has a central role in ER-associated proteolysis.
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PMID:Ubx2 links the Cdc48 complex to ER-associated protein degradation. 1617 53

The FtsH proteases, also called AAA proteases, are membrane-bound ATP-dependent metalloproteases. The Arabidopsis genome contains a total of 12 FtsH-like genes. Two of them, AtFtsH4 and AtFtsH11, encode proteins with a high similarity to Yme1p, a subunit of the i-AAA complex in yeast mitochondria. Phylogenetic analysis groups the AtFtsH4, AtFtsH11 and Yme1 proteins together, with AtFtsH4 being the most similar to Yme1. Using immunological method we demonstrate here that AtFtsH4 is an exclusively mitochondrial protein while AtFtsH11 is found in both chloroplasts and mitochondria. AtFtsH4 and AtFtsH11 proteases are integral parts of the inner mitochondrial membrane and expose their catalytic sites towards the intermembrane space, same as yeast i-AAA. Database searches revealed that orthologs of AtFtsH4 and AtFtsH11 are present in both monocotyledonous and dicotyledonous plants. The two plant i-AAA proteases differ significantly in their termini: the FtsH4 proteins have a characteristic alanine stretch at the C-terminal end while FtsH11s have long N-terminal extensions. Blue-native gel electrophoresis revealed that AtFtsH4 and AtFtsH11 form at least two complexes with apparent molecular masses of about 1500 kDa. This finding implies that plants, in contrast to fungi and metazoa, have more than one complex with a topology similar to that of yeast i-AAA.
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PMID:Plant mitochondria contain at least two i-AAA-like complexes. 1624 55

Escherichia coli FtsH, which belongs to the AAA (ATPases associated with diverse cellular activities) family, is an ATP-dependent and membrane-bound protease. FtsH degrades misassembled membrane proteins and a subset of cytoplasmic regulatory proteins. It has been proposed that ATP-dependent proteases unfold substrate proteins and initiate a processive proteolysis from either terminus of the substrate polypeptide. We have found that FtsH degrades E. coli apo-flavodoxin (apo-Fld) but not holo-Fld containing non-covalently bound flavin mononucleotide (FMN). A mutant Fld carrying a substitution of Tyr94 to Asp (Fld(YD)) with a lower affinity for FMN was efficiently degraded by FtsH. To elucidate the directionality of Fld(YD) degradation by FtsH, we constructed several Fld(YD) fusion proteins with glutathione S-transferase (GST), green fluorescent protein (GFP), or both GST and GFP. It was found that FtsH was able to initiate degradation of the Fld(YD) moiety even when it was sandwiched by GST and GFP. Evidence indicated that FtsH can initiate proteolysis of GST-Fld(YD)-GFP from the Fld(YD) moiety by translocating an internal loop to the protease chamber in an ATP-dependent manner and that, at least, the proteolysis in the C to N direction proceeds processively.
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PMID:An AAA protease FtsH can initiate proteolysis from internal sites of a model substrate, apo-flavodoxin. 1648 14

Two membrane-bound ATP-dependent AAA proteases conduct protein quality surveillance in the inner membrane of mitochondria and control crucial steps during mitochondrial biogenesis. AAA domains of proteolytic subunits are critical for the recognition of non-native membrane proteins which are extracted from the membrane bilayer for proteolysis. Here, we have analysed the role of the conserved loop motif YVG, which has been localized to the central pore in other hexameric AAA(+) ring complexes, for the degradation of membrane proteins by the i-AAA protease Yme1. Proteolytic activity was found to depend on the presence of hydrophobic amino acid residues at position 354 within the pore loop of Yme1. Mutations affected proteolysis in a substrate-specific manner: whereas the degradation of misfolded membrane proteins was impaired at a post-binding step, folded substrate proteins did not interact with mutant Yme1. This reflects most likely deficiencies in the ATP-dependent unfolding of substrate proteins, since we observed similar effects for ATPase-deficient Yme1 mutants. Our findings therefore suggest an essential function of the central pore loop for the ATP-dependent translocation of membrane proteins into a proteolytic cavity formed by AAA proteases.
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PMID:Substrate specific consequences of central pore mutations in the i-AAA protease Yme1 on substrate engagement. 1652 90

Misfolded proteins of the endoplasmic reticulum (ER) are targeted to the cytoplasm for proteasomal degradation. Key components of this process are ER membrane-bound ubiquitin ligases. These ligases associate with the cytoplasmic AAA-ATPase Cdc48p/p97, which is thought to support the release of malfolded proteins from the ER. Here, we characterize a yeast protein complex containing the ubiquitin ligase Hrd1p and the ER membrane proteins Hrd3p and Der1p. Hrd3p binds malfolded proteins in the ER lumen enabling their delivery to downstream components. Therefore, we propose that Hrd3p acts as a substrate recruitment factor for the Hrd1p ligase complex. Hrd3p function is also required for the association of Cdc48p with Hrd1p. Moreover, our data demonstrate that recruitment of Cdc48p depends on substrate processing by the Hrd1p ligase complex. Thus, the Hrd1p ligase complex unites substrate selection in the ER lumen and polyubiquitination in the cytoplasm and links these processes to the release of ER proteins via the Cdc48p complex.
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PMID:The Hrd1p ligase complex forms a linchpin between ER-lumenal substrate selection and Cdc48p recruitment. 1661 26

The peroxisomal targeting signal type1 (PTS1) receptor Pex5 is required for the peroxisomal targeting of most matrix proteins. Pex5 recognises target proteins in the cytosol and directs them to the peroxisomal membrane where cargo is released into the matrix, and the receptor shuttles back to the cytosol. Recently, it has become evident that the membrane-bound Pex5 can be modified by mono- and polyubiquitination. This review summarises recent results on Pex5 ubiquitination and on the role of the AAA peroxins Pex1 and Pex6 as dislocases required for the release of Pex5 from the membrane to the cytosol where the receptor is either degraded by proteasomes or made available for another round of protein import into peroxisomes.
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PMID:Peroxisomal matrix protein receptor ubiquitination and recycling. 1702 12


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