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 ftsH gene of Mycobacterium smegmatis SN2 (MsftsH) was cloned from two independent partial genomic DNA libraries and characterized, along with the identification of ephA and folE as the neighbouring upstream and downstream genes respectively. The genomic organization of the MsftsH locus was found to be identical to that of the Mycobacterium tuberculosis ftsH gene (MtftsH) and similar to that of other bacterial genera, but with divergence in the upstream region. The MsftsH gene is 2.3 kb in size and encodes the AAA (ATPases Associated with diverse cellular Activities) family Zn(2+)-metalloprotease FtsH (MsFtsH) of 85 kDa molecular mass. This was demonstrated from the expression of the full-length recombinant gene in Escherichia coli JM109 cells and from the identification of native MsFtsH in M. smegmatis SN2 cell lysates by Western blotting with anti-MtFtsH and anti-EcFtsH antibodies respectively. The recombinant and the native MsFtsH proteins were found localized to the membrane of E. coli and M. smegmatis cells respectively. Expression of MsFtsH protein in E. coli was toxic and resulted in growth arrest and filamentation of cells. The MsftsH gene did not complement lethality of a DeltaftsH3 : : kan mutation in E. coli, but when expressed in E. coli cells, it efficiently degraded conventional FtsH substrates, namely sigma(32) protein and the protein translocase subunit SecY, of E. coli cells.
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PMID:Genomic organization and in vivo characterization of proteolytic activity of FtsH of Mycobacterium smegmatis SN2. 1528 59

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

We have previously reported a new group of AAA proteins, which is only found in Archaeoglobus and methanogenic archaea (AMA). The proteins are phylogenetically basal to the metalloprotease clade and their N-terminal domain is homologous to the beta-clam part of the N-domain of CDC48-like proteins. Here we report the biochemical and biophysical characterization of Archaeoglobus fulgidus AMA, and of its isolated N-terminal (AMA-N) and ATPase (AMA-DeltaN) domains. AfAMA forms hexameric complexes, as does AMA-N, while AMA-DeltaN only forms dimers. The ability to hexamerize is dependent on the integrity of a GYPL motif in AMA-N, which resembles the pore motif of FtsH and HslU. While the physiological function of AMA is unknown, we show that it has ATP-dependent chaperone activity and can prevent the thermal aggregation of proteins in vitro. The ability to interact with non-native proteins resides in the N-domain and is energy-independent.
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PMID:Characterization of AMA, a new AAA protein from Archaeoglobus and methanogenic archaea. 1673 Apr 57

The hexameric membrane-spanning ATP-dependent metalloprotease FtsH is universally conserved in eubacteria, mitochondria, and chloroplasts, where it fulfills key functions in quality control and signaling. As a member of the self-compartmentalizing ATPases associated with various cellular activities (AAA+ proteases), FtsH converts the chemical energy stored in ATP via conformational rearrangements into a mechanical force that is used for substrate unfolding and translocation into the proteolytic chamber. The crystal structure of the ADP state of Thermotoga maritima FtsH showed a hexameric assembly consisting of a 6-fold symmetric protease disk and a 2-fold symmetric AAA ring. The 2.6 A resolution structure of the cytosolic region of apo-FtsH presented here reveals a new arrangement where the ATPase ring shows perfect 6-fold symmetry with the crucial pore residues lining an open circular entrance. Triggered by this conformational change, a substrate-binding edge beta strand appears within the proteolytic domain. Comparison of the apo- and ADP-bound structure visualizes an inward movement of the aromatic pore residues and generates a model of substrate translocation by AAA+ proteases. Furthermore, we demonstrate that mutation of a conserved glycine in the linker region inactivates FtsH.
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PMID:The crystal structure of apo-FtsH reveals domain movements necessary for substrate unfolding and translocation. 1995 24

Autosomal dominant spinocerebellar ataxias (SCAs) are genetically heterogeneous neurological disorders characterized by cerebellar dysfunction mostly due to Purkinje cell degeneration. Here we show that AFG3L2 mutations cause SCA type 28. Along with paraplegin, which causes recessive spastic paraplegia, AFG3L2 is a component of the conserved m-AAA metalloprotease complex involved in the maintenance of the mitochondrial proteome. We identified heterozygous missense mutations in five unrelated SCA families and found that AFG3L2 is highly and selectively expressed in human cerebellar Purkinje cells. m-AAA-deficient yeast cells expressing human mutated AFG3L2 homocomplex show respiratory deficiency, proteolytic impairment and deficiency of respiratory chain complex IV. Structure homology modeling indicates that the mutations may affect AFG3L2 substrate handling. This work identifies AFG3L2 as a novel cause of dominant neurodegenerative disease and indicates a previously unknown role for this component of the mitochondrial protein quality control machinery in protecting the human cerebellum against neurodegeneration.
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PMID:Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. 2073 32

A comparative proteomics analysis was performed to identify the molecular response of a rice cultivar (Oryza sative cv. 'IRRI71331') with high phosphorous (P) uptake efficiency to low P stress. The hydroponically grown rice plants were provided with two levels of P (0.5 mg x L(-1) and 10 mg x L(-1)) supplied in quarter strength Kimura solution, and the root total proteins extracted on the 3rd and 6th day of treatments were separated by two-dimensional gel electrophoresis (2-DE). Comparing with the control (10 mg x L(-1) of P), a total of 29 protein spots under low P stress (0.5 mg x L(-1)) showed differences in their relative abundance, among which, 17 were higher, 11 were lower, and 1 was novel on the 3rd day, and 8 were induced, 19 were suppressed, 1 was disappeared, and 1 had no obvious change on the 6th day. Ten differentially expressed protein spots were identified by MALDI-TOF/MS, and searched in protein databases. According to the putative functions, the identified proteins were classified into four groups, i.e., signal transduction (glycine-rich RNA-binding protein, phosphate starvation response regulator-like), gene expression (putative pre-mRNA splicing factor, putative AAA-metalloprotease), metabolism (adenylosuccinate lyase, serpin, S-adenosylmethionine synthetase, MYB transcription factor-like protein), and ion transport (cation-transporting ATPase, sarcoplasmic reticulum protein). The identified proteins were involved in various physiological responses to enhance stress resistance, such as signal recognition and transduction, RNA cleavage, degradation of denatured protein, and ion transportation and cellular ion balance. The serine protease inhibitor and S-adenosylmethionine synthetase and the MYB transcription factor-like protein, which were the key proteins associated with P deficiency--tolerance of other species, were affected by the same stress for rice. The results indicated that the tolerance to low P stress was controlled by a complex signal transduction and metabolism regulation network in rice root system.
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PMID:[Differential protein analysis on the root response of rice with high phosphorous uptake efficiency to low phosphorous stress]. 2144 14

FtsHs are a well-characterized family of membrane bound proteases containing an AAA (ATPase associated with various cellular activities) and a Zn(2+) metalloprotease domain. FtsH proteases are found in eubacteria, animals and plants and are known to have a crucial role in housekeeping proteolysis of membrane proteins. In Arabidopsis thaliana, 12 FtsH family members are present (FtsH 1-12) and their subcellular localization is restricted to mitochondria and chloroplasts. In addition, five genes coding for proteins homologous to FtsH (FtsHi 1-5) have been detected in the genome, lacking the conserved zinc-binding motif HEXXH, which presumably renders them inactive for proteolysis. These inactive FtsHs as well as nine of the active FtsHs are thought to be localized in the chloroplast. In this article, we shortly summarize the recent findings on plastidic FtsH proteases in text and figures. We will mainly focus on FtsH 1, 2, 5 and 8 localized in the thylakoid membrane and known for their importance in photosynthesis.
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PMID:FtsH proteases located in the plant chloroplast. 2212 66

This study provides the first direct evidence for the dual role of the metalloprotease FtsH in membrane protein biogenesis. Using the physiological substrate DrrAB, it is shown that FtsH is not only responsible for proteolysis of unassembled DrrB protein but also plays a much broader role in biogenesis of the DrrAB complex. Previous studies showed that the stable expression of DrrB in the membrane depends on simultaneous expression of DrrA. Here we show that DrrB is proteolyzed by FtsH when it is expressed alone. Moreover, DrrA and DrrB proteins expressed together in a temperature-sensitive ftsH mutant strain of Escherichia coli were found to be nonfunctional due to their incorrect assembly. Simultaneous expression of wild-type FtsH in trans resulted in normal doxorubicin efflux. Strikingly, doxorubicin efflux could be restored in mutant cells irrespective of whether FtsH was expressed simultaneously with DrrAB or expressed after these proteins had already accumulated in an inactive conformation, thus providing crucial evidence for the ability of FtsH to refold the misassembled proteins. Complementation experiments also showed that the catalytic AAA domain of FtsH contains a chaperone-like activity, however, unlike wild-type FtsH, it was unable to restore function. Our results therefore show for the first time that FtsH contains the protease as well as refolding functions, and both the AAA and the proteolytic domains of FtsH are required for each of these activities.
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PMID:Dual role of the metalloprotease FtsH in biogenesis of the DrrAB drug transporter. 2350 16

Sumoylation during genotoxic stress regulates the composition of DNA repair complexes. The yeast metalloprotease Wss1 clears chromatin-bound sumoylated proteins. Wss1 and its mammalian analog, DVC1/Spartan, belong to minigluzincins family of proteases. Wss1 proteolytic activity is regulated by a cysteine switch mechanism activated by chemical stress and/or DNA binding. Wss1 is required for cell survival following UV irradiation, the smt3-331 mutation and Camptothecin-induced formation of covalent topoisomerase 1 complexes (Top1cc). Wss1 forms a SUMO-specific ternary complex with the AAA ATPase Cdc48 and an adaptor, Doa1. Upon DNA damage Wss1/Cdc48/Doa1 is recruited to sumoylated targets and catalyzes SUMO chain extension through a newly recognized SUMO ligase activity. Activation of Wss1 results in metalloprotease self-cleavage and proteolysis of associated proteins. In cells lacking Tdp1, clearance of topoisomerase covalent complexes becomes SUMO and Wss1-dependent. Upon genotoxic stress, Wss1 is vacuolar, suggesting a link between genotoxic stress and autophagy involving the Doa1 adapter.
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PMID:Wss1 metalloprotease partners with Cdc48/Doa1 in processing genotoxic SUMO conjugates. 2634 35

The intraluminal thrombus (ILT) of human abdominal aortic aneurysm (AAA) has been suggested to damage the underlying aortic wall, but previous work found scant activity of soluble proteases in the abluminal layer of the ILT, adjacent to the aneurysm. We hypothesised that transmembrane proteases carried by membrane microvesicles (MV) from dying cells remain active in the abluminal ILT. ILTs and AAA segments collected from 21 patients during surgical repair were assayed for two major transmembrane proteases, ADAM10 (a disintegrin and metalloprotease-10) and ADAM17. We also exposed cultured cells to tobacco smoke and assessed ADAM10 and ADAM17 expression and release on MVs. Immunohistochemistry showed abundant ADAM10 and ADAM17 protein in the ILT and underlying aneurysmal aorta. Domain-specific antibodies indicated both transmembrane and shed ADAM17. Importantly, ADAM10 and ADAM 17 in the abluminal ILT were enzymatically active. Electron microscopy of abluminal ILT and aortic wall showed MVs with ADAM10 and ADAM17. By flow cytometry, ADAM-positive microvesicles from abluminal ILT carried the neutrophil marker CD66, but not the platelet marker CD61. Cultured HL60 neutrophils exposed to tobacco smoke extract showed increased ADAM10 and ADAM17 content, cleavage of these molecules into active forms, and release of MVs carrying mature ADAM10 and detectable ADAM17. In conclusion, our results implicate persistent, enzymatically active ADAMs on MVs in the abluminal ILT, adjacent to the aneurysmal wall. The production of ADAM10- and ADAM17-positive MVs from smoke-exposed neutrophils provides a novel molecular mechanism for the vastly accelerated risk of AAA in smokers.
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PMID:Proteolytically active ADAM10 and ADAM17 carried on membrane microvesicles in human abdominal aortic aneurysms. 2642 58


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