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• W1569886462 abstract "A conference entitled ‘Proteolysis in Prokaryotes: Protein Quality Control and Regulatory Principles’ was organized by Regine Hengge and Bernd Bukau from 25–27 October, 2002 in Schwetzingen, a small southern German town with a reputation for its castle and asparagus. It was the first conference sponsored by the Deutsche Forschungsgemeinschaft (DFG) as part of a 6 year priority programme to support research in this field. The scientific programme covered the molecular mechanisms of proteolytic systems, including protease and chaperone structures as well as molecular recognition, unfolding and processing of substrates. Complementary to this biochemical view of proteolysis, the physiology and biodiversity of proteolytic processes in prokaryotes, mitochondria and chloroplasts were covered with a particular focus on the recently emerging roles of proteolysis in the complex regulation of stress responses, cell cycle and development. The cellular proteases with a major function in protein quality control and regulation have a number of features in common: (i) they recognize many different substrate proteins that range from denatured polypeptides to key regulatory proteins in a fully native state, i.e. substrate recognition is at the same time highly flexible and highly specific; (ii) they form multisubunit barrel-like complexes, with the active sites sequestered inside with entry tightly controlled by chaperone subunits; (iii) for the cytosolic proteases, unfolding and translocation into the proteolytic chamber requires ATP hydrolysis; and (iv) substrate degradation is processive, i.e. complete (for recent reviews, see Dougan et al., 2002a; Jenal and Hengge-Aronis, 2003). Recent research has focussed on three model systems, i.e. the cytosolic Clp proteases, the membrane-bound FtsH (HflB) protease and the periplasmic DegP (HtrA) protease. The ClpXP and ClpAP proteases each consist of two seven-subunit ClpP rings that form the proteolytic chamber and six-subunit ClpX or ClpA rings attached at both ends that bind and unfold substrates (Guo et al., 2002a; Wang et al., 1997). Electron microscopy has been used to locate protein substrate binding sites at the outer ring surface in ClpXP and ClpAP complexes (Mike Maurizi, NIH, Bethesda, USA). Direct binding measurements with several substrate proteins (λO protein, RepA, GFP-SsrA) indicate that only one protein molecule binds per ClpX or ClpA ring at a time. Surprisingly, small peptides containing ClpA or ClpX recognition tags also bind with a stoichiometry of one peptide per ClpA6 or ClpX6. Two models can explain these data: all six subunits contribute to a single binding site centrally located on a hexamer, or binding sites are located on each subunit but display high negative cooperativity. Cross-linking with peptide substrates is underway to distinguish between these models and to identify the regions of ClpA and ClpX that make up the binding sites. To date, only a handful of cellular substrates of ClpXP and ClpAP have been identified. Using a tagged and inactive variant of ClpP (ClpPtrap), substrates for ClpXP and ClpAP were trapped in vivo, purified and identified by mass spectrometry (reported by Briana Burton, from Tania Baker's laboratory, MIT, Cambridge, USA; Flynn et al., 2003). The trapped proteins include transcription factors, metabolic enzymes and proteins involved in the starvation and oxidative stress responses. Analysis of the newly identified ClpXP substrates provided insight into the mechanisms of substrate recognition. Sequence analysis, binding studies, fusion proteins and mutagenesis revealed the presence of two related C-terminal motifs and three related N-terminal motifs that may be recognized by ClpX. Nearly all of the trapped substrates have one or more of the recognition signals (Flynn et al., 2003). Use of the ClpPtrap also revealed that some substrate proteins (e.g. the SOS-regulator LexA) are recognized only after they are initially cleaved by another protease. RecA-induced autocleavage uncovers recognition signals in the two separated protein domains that render the LexA protein fragments susceptible to ClpXP-dependent proteolysis in vivo and in vitro (Neher et al., 2003). Additional recognition or targeting factors, whose expression and/or activity can be regulated by intra- or extracellular signals, help to ensure that degradation of specific substrates occurs at the right time and place (Dougan et al., 2002a). Proteolysis of the general stress sigma factor σS or RpoS (which occurs in rapidly growing cells but is inhibited by various stress conditions) requires initial direct binding by the phosphorylated response regulator RssB (Becker et al., 1999; Klauck et al., 2001; Zhou et al., 2001). Recognition of σS by the RssB/ClpXP proteolytic machinery is a complex process involving at least two distinct regions in σS (Fig. 1; R Hengge, Freie Universität, Berlin, Germany). Region 2.5 of σS, which forms a long α helix, is sufficient for binding of phosphorylated RssB. In addition, a region close to the N-terminus acts as a binding site for ClpX6. Native σS, however, is not bound by ClpX6. Interaction of each factor with its respective binding site alone is not sufficient to trigger degradation of σS or σS-derived reporter proteins. These data indicate the following sequence of events: RssB initially interacts with σS and triggers a change of conformation that exposes the ClpX6-binding site close to the N-terminus. Once σS is bound to ClpX6, RssB plays a second role (either in unfolding or during the beginning transfer of unfolded σS into the ClpXP protease), before it is released from the complex and σS is completely degraded. Experiments reported by Susan Gottesmann (NIH) suggest that a region near or at the C-terminus of the output domain of RssB might play a role in this process that goes beyond σS binding. She reported that deletions that remove 25–100 amino acids from the C-terminus apparently sequester σSin vivo, with the consequence that σS becomes stable but inactive. Surprisingly, this inhibition of activity requires both ClpX and ClpP, suggesting that a stable σS–RssB–ClpXP protease complex forms but is unable to release σS for degradation by ClpXP. Consistent with a critical role for phosphorylation in the interaction of RssB and σS and with a physiologically relevant interaction of RssB and σS in the C-terminally deleted mutants, a C-terminally deleted derivative of RssB that also lacks the phosphorylation site (D58P) no longer sequestered σS. Interaction of σS(RpoS) and RpoS::LacZ hybrid proteins with the recognition factor RssB and the hexameric ClpX chaperone (provided by R. Hengge, Freie Universität, Berlin). Numbers refer to the common nomenclature for functional regions in sigma factors. NTE: N-terminal element for ClpX6 recognition. For other details, see text. The SspB protein also serves as a specificity factor for the ClpXP protease by specifically stimulating proteolysis of proteins bearing an SsrA tag. The SsrA tag is an 11 residue peptide that is added co-translationally to the C-terminus of polypeptides whose biosynthesis has been stalled (Karzai et al., 2000). SspB enhances binding of tagged substrates to ClpX and stimulates their unfolding by ClpX and their degradation by ClpXP (Levchenko et al., 2000). SspB protein is a stable homodimer with two independent binding sites for SsrA-tagged substrates. SspB itself binds to ClpX and stimulates its ATPase activity. The mechanism of substrate delivery involves the formation of a tertiary complex consisting of a ClpX hexamer, a SspB dimer and two SsrA-tagged substrate proteins (Wah et al., 2002). As reported by Igor Levchenko (MIT, Cambridge, USA), the crystal structure of Haemophilus influenzae SspB protein at 1.8 Å resolution (Fig. 2) reveals that the SspB dimer is 65 Å wide in its maximal dimension. The dimerization interface of the protein is formed by hydrophobic contacts between two amino-terminal α-helices. The core domain of each monomer of SspB is formed by two four-stranded β-sheets. At the extreme ends of each dimer there is a well-defined hydrophobic ‘cleft’ formed by one of the β-strands and two loop structures. This cleft is involved in crystallographic contact with the C-terminus of the neighbouring SspB dimer, where the backbone atoms of Asn53 in the cleft interact with the side-chain of Gln120. This cleft–peptide interaction has been observed in two independent crystal forms, and probably reflects an interaction important in forming the SspB–SsrA complex. Structure of the SspB dimer with the SsrA tag peptide modelled into hydrophobic clefts at opposite ends of the dimer (provided by I. Levchenko, R. Grant and T. Baker; MIT). ClpA, ClpB and ClpC are representatives of the typical HSP100 protein family, which are chaperones with two ATPase domains. These chaperones can cooperate with specific adaptor proteins or specificity factors. ClpS is such a factor for the ClpA chaperone that improves recognition of denatured proteins by ClpA (Dougan et al., 2002b). A 2.5 Å resolution crystal structure of ClpS in a complex with the N-terminal domain of ClpA (Fig. 3A) was recently determined (Guo et al., 2002b; Zeth et al., 2002). Using mutagenesis, it was demonstrated that two contact residues (Glu 79 and Lys 84) are essential not only for ClpAS complex formation but also for ClpAPS-mediated substrate degradation. The corresponding residues are absent from ClpB, providing a structural rationale for the unique specificity exhibited by ClpS despite the high overall similarity between ClpA and ClpB. In order to elucidate the location of ClpS within the ClpA hexamer, the N-terminal domain of ClpA was modelled onto a structurally defined, homologous, AAA+ protein (Fig. 3B). From this model, a molecular mechanism to explain the ClpS-mediated switch in ClpA substrate specificity has been suggested (Kornelius Zeth, Max Planck Institute, Martinsried, Germany, in collaboration with David Dougan and Bernd Bukau, ZMBH, Heidelberg, Germany). Structure of a complex between ClpS and the N-terminal domain of ClpA (A) as well as a model of hexameric ClpA with ClpS subunits attached shown as side and top views (B) (provided by K. Zeth, MPI Martinsried). The ClpA6 model was generated by superposition onto the related AAA-protein hexameric NSF protein; Yu et al., 1998). Axel Mogk and Bernd Bukau (ZMBH, Heidelberg, Germany) reported novel results on the roles of chaperones in the removal of heat-aggregated proteins in the Escherichia coli cytosol. A ‘bi-chaperone’, consisting of ClpB and the DnaK system (KJE), mediates the solubilization and refolding of aggregated proteins. The intercalation of small heat shock proteins (sHSPs) into protein aggregates accelerated the ClpB/KJE-mediated resolubilization process in vitro and enabled the DnaK system to disaggregate small protein aggregates even in the absence of ClpB. Consistent with these findings, E. coliΔibpAB mutant strains, lacking sHSP function, exhibited delayed protein disaggregation and reduced thermotolerance, and sHSP function became essential at higher growth temperatures when DnaK levels were low. Mogk and Bukau furthermore reported on the identification of a ClpB trap mutant. This mutant has alterations in both Walker B motifs, thereby abolishing ATPase activity without affecting the overall structure (Mogk et al., 2003). The ClpB mutant protein interacted in a stable manner with substrates in an ATP-dependent way and strongly inhibited the KJE-dependent dissociation of sHSP/substrate complexes. ClpC is an HSP100 protein involved in general stress survival of Bacillus subtilis. A complex of ClpC with the protease ClpP and the adaptor protein MecA controls competence development by regulated proteolysis of the master regulator ComK (Turgay et al., 1998; Persuh et al., 1999). Also the major chaperone activities of ClpC were found to require MecA. In particular, MecA enabled ClpC to disaggregate and refold protein aggregates (Schlothauer et al., 2003). Finally, MecA enabled the subsequent degradation of unfolded or previously heat-aggregated proteins by ClpCP while native protein was not degraded. This study demonstrates that adaptor proteins such as MecA, interacting with their cognate HSP100/Clp proteins, are not restricted to specific regulatory tasks (Kürsad Turgay, ZMBH, Heidelberg, Germany). After capture of substrate proteins, complex ATP-dependent proteases have to carry out three major tasks: substrate unfolding, translocation and degradation. These activities were studied in real-time using ClpAP, fluorescent model protein substrates and fluorescence resonance energy transfer (FRET) technology (Eilika Weber-Ban, ETH, Zürich, Switzerland). To probe the unfolding reaction, a double cysteine mutant of the N-terminal λ-repressor domain (in λR-SsrA) was made with the cysteines at opposite ends of the primary structure, but close in the native structure. To follow the degradation reaction, the cysteines were placed close together on the primary structure, but far enough apart that cleavage occurs in between. By labelling the two cysteines with fluorophores forming a FRET pair, the unfolding and degradation reaction could be followed via a decrease in FRET efficiency. An unfolding phase and a slow refolding phase due to release of substrate from ClpA-binding sites could be detected in the absence of active ClpP. With ClpA and inactive ClpP, λR-SsrA refolds inside the ClpP cavity. The degradation reaction proceeds with a fourfold longer lag phase compared with the unfolding reaction. With ATPγS, λR-SsrA is unfolded very slowly and to near completion and stays bound to ClpA in an unfolded conformation over extended periods of time. Although not related at the amino acid sequence level, bacterial Clp proteases and the eukaryotic and archaeal proteasome have analogous structure and function. The 19S component of the 26S proteasome contains six ATPase subunits. To clarify how they unfold and translocate proteins into the 20S proteasome for degradation, the homologous proteasome-regulatory ATPase complex from archaea, PAN, and the globular substrate GFP-SsrA were studied (Ami Navon from A. Goldberg's laboratory, Harvard Medical School, Boston, USA). Using small or large tags (Biotin and Biotin-Avidin respectively) attached near its N- or C-termini, GFP-SsrA was found to require threading through the ATPase in a C to N direction. Moreover, translocation does not cause but follows ATP-dependent unfolding, which occurs on the surface of the ATPase ring (Navon and Goldberg, 2001). However, using various proteins blocked at either end, the PAN 20S complex and also the mammalian 26S proteasome were found to degrade certain proteins (e.g. casein) starting only from the N terminus, and certain other proteins (e.g. calmodulin) in both directions. Surprisingly, when the globular GFP domain was fused upstream or downstream of a readily degradable polypeptide, the GFP portion of the fusion was not degraded and was released in a folded form. Thus, the direction of translocation and degradation found with different substrates and also the capacity of the proteasomal ATPase to unfold a globular domain appears to be determined by the properties of the protein's terminal regions or by the location of a specific degradation signal. The crystal structure of the ATPase domain of FtsH (HflB) was determined and a hexamer form was modelled, providing insights into possible modes of nucleotide binding and intersubunit catalysis (Fig. 4; Krzywda et al., 2002). In the hexameric ring, there is a conserved aromatic residue, Phe228 in FtsH, which lines the central pore. The function of Phe228 was probed by constructing FtsH mutants in which Phe228 is replaced by each of the 19 other common amino acids. Functional assays indicated that bulkier uncharged/non-polar residues at this position are essential for retention of activity, suggesting an involvement of Phe228 in threading unfolded polypeptides through the enzyme's central pore (Teru Ogura, Kumamoto University, Japan). Top and side views of a modelled hexamer of the ATPase domain of FtsH. Each protomer is coloured differently, while bound ATPs are shown in red (provided by Teru Ogura, Kumamoto University). The mechanistic functions of the FtsH protease as well as its role in membrane protein quality control were summarized by Koreaki Ito (Kyoto University, Japan) (Fig. 5). The processive dislocation/proteolysis reaction by FtsH can be initiated either from the N- or from the C-terminal tail of a membrane protein that protrudes sufficiently into the cytosol. Proton-motive force stimulates the degradation process, which can be reconstituted in proteoliposomes (Akiyama and Ito, 2003). In wild-type cells, FtsH exists exclusively as an exceptionally large complex with HflKC, termed ‘holo-enzyme’. FtsH cooperates with the membrane-integrated metallo-protease HtpX, as suggested by the synthetic lethality of the loss of FtsH and HtpX. The latter is under the control of the Cpx extracytoplasmic stress response pathway, which responds to abnormal cytoplasmic membrane proteins. Cooperation between two membrane-associated proteases, DegS and YaeL, has also been observed for the degradation of the anti-σE factor RseA, which results in the activation of the σE-dependent extracytoplasmic stress response (Alba et al., 2002; Kanehara et al., 2002). Proteolytic systems in the E. coli plasma membrane (provided by K. Ito, Kyoto University; for details, see text). Classic soluble FtsH substrates are the heat shock sigma factor σ32 and the CII regulator, which plays a key role in the phage lysis-lysogeny decision of phage lambda. While membrane proteins can be degraded from either end, truncation analyses showed that the termini of σ32 (RpoH) are not essential for degradation by FtsH. Analysis of hybrid proteins between E. coliσ32 and a comparatively stable σ32 variant from Bradyrhizobium japonicum revealed that an internal region in the N-terminal part of RpoH was found to be required for rapid turnover (Franz Narberhaus, ETH, Zürich, Switzerland). Amos Oppenheim (Hebrew University, Jerusalem, Israel) provided evidence that the conserved C-terminal end of CII acts as a necessary and sufficient cis-acting target for rapid proteolysis. Deletions of this conserved tag or mutations that add two aspartate residues at the C-terminus of the tag do not affect the structure or regulatory activity of CII but the mutations abrogate CII degradation by FtsH. Another λ protein, CIII, protects CII from degradation in vivo. An in vitro assay for the lambda CIII protein demonstrated that CIII directly inhibits proteolysis by FtsH to protect CII from degradation. CIII also inhibits the proteolysis of a number of other FtsH substrates. The region coding for the C-terminal end of CII overlaps with a gene that encodes a small antisense RNA called OOP. Expression of OOP decreases CII mRNA stability. Deletion of the end of the cII gene could prevent OOP RNA (supplied in trans) interference with the CII requirement in the lysogenic pathway. These findings provide the first example of a gene that carries a region that modulates stability both at the mRNA and protein levels (Kobiler et al., 2002). The widely conserved DegP (HtrA) family of proteins consists of ATP-independent serine proteases. Some, but not all, of the 180 family members are classic heat shock proteins. They are typically localized in extracytoplasmic compartments such as the periplasm of Gram-negative bacteria, the ER of eukaryotes and the chloroplasts of plants. Prokaryotic DegPs are involved in thermal, osmotic, hydrogen peroxide and pH tolerance, as well as in virulence. The defining feature of the HtrA family is the combination of a catalytic domain with one or more C-terminal PDZ domains (Clausen et al., 2002). The large variety of known substrates indicates that DegP is a key factor controlling protein metabolism in the cell envelope. DegP of E. coli has both chaperone and protease activities. These functions are switching in a temperature-dependent manner, the protease activity being most apparent at elevated temperatures (Spiess et al., 1999). The crystal structure of DegP was solved (Krojer et al., 2002). Staggered association of trimeric rings forms the DegP hexamer (Fig. 6). The proteolytic sites are located in a central cavity that is accessible only laterally. The mobile side walls are formed by 12 PDZ domains, which mediate the opening and closing of the particle and probably the initial binding of substrate. Several hydrophobic patches that act as docking sites for unfolded polypeptides line the inner cavity. In the chaperone conformation, the protease domain of DegP exists in an inactive state, in which substrate binding as well as catalysis are abolished (Michael Ehrmann, Cardiff University, UK, and Tim Clausen, Max Planck Institute, Martinsried, Germany). In addition, the complex between DegP and the protease inhibitor DFP could be crystallized. Preliminary structural data suggest that DegP, as present in the complex, represents the protease state. The protease form should be helpful to deduce structural determinants for substrate specificity and for the switch in activity. Remarkably, Tim Clausen reported that the temperature dependence of this switch can also be observed in the crystalline state. Open and closed forms of DegP in the chaperone conformation (provided by T. Clausen, MPI Martinsried). The N-terminal domains are shown in blue, the protease domains in green and the PDZ1 and PDZ2 domains in red and yellow respectively. A major housekeeping function for proteolysis is obviously the disposal of non-functional proteins. These can be denatured and aggregated polypeptides, where the cell has to make the decision between ‘repair’, i.e. disaggregation and refolding, or degradation of the ‘hopeless’ cases. This is believed to occur by kinetic partitioning between chaperones (e.g. GroEL/ES or ClpB/DnaK, see above) and chaperone/protease systems (e.g. ClpAP). Other housekeeping problems are incomplete polypeptides generated from partially degraded or damaged mRNAs. In such cases, the ribosomes stall and are released by the SsrA tagging system, which co-translationally adds a tag to polypeptides arrested during their biosynthesis. The resulting fusion proteins are directed to degradation by the SspB/ClpXP protease (Karzai et al., 2000). It recently became clear that SsrA tagging can also occur on full-length proteins (Collier et al., 2002; Roche and Sauer, 2002). A change from a weak to a strong translational stop sequence in the mRNA for ribokinase (UGAc to UAAu) annihilated SsrA-tagging. The efficiency of tagging was inversely correlated with translational termination efficiency, revealing a dynamic competition. Both the nature of the stop sequence and the presence of rare codons in its vicinity diminished the efficiency of translational termination of the ribokinase messenger, allowing readthrough and frameshifting events to occur. It is proposed that an additional function of SsrA-tagging is to prevent translational recoding at inefficient termination sites, thereby avoiding the formation of extended proteins (Justine Collier from Philippe Bouloc's laboratory, Université Paris-Sud, France). Proteolysis can be important to adjust the activity of an essential biosynthetic pathway, and thereby the growth rate, to the overall physiological situation. The first enzyme in methionine biosynthesis in E. coli (homoserine transsuccinylase, HTS) has a short half-life and is thermally unstable (Gur et al., 2002). It is therefore a useful model to study proteolysis, as well as stabilization of proteins by chaperones at physiological growth temperatures (above 37°C). The amino terminal part of the molecule is a degradation signal for proteases and the enzyme becomes stable only in triple lon, clpP, hslVU mutants. The DnaK complex prevents inactivation and aggregation. Rescue from aggregates requires DnaK, GrpE and ClpB. However, it was shown that aggregated HTS occurs in dnaJ mutants, a finding subsequently extended to other aggregated proteins (Eliora Ron, Tel.:Aviv University, Israel). Plasmid maintenance systems also often depend on proteolysis. In the P1 plasmid system, the unstable antitoxin, Phd, which antagonizes the toxin Doc, is a ClpXP substrate. In experiments reported by Maciej Zylicz (International Institute of Molecular and Cell Biology, Warsaw, Poland), the genetic and biochemical behaviour of two ClpX mutant proteins, both mutated at the ATP-binding site, namely K125T and T126A, was investigated. In vivo the ClpX(T126A) mutant protein exhibits no activity in the P1 plasmid system and, as a consequence, cured cells are not killed. In contrast, ClpX(K125T) exhibits wild-type activity in vivo, i.e. cured cells are selectively killed. In contrast to their in vivo behaviour, neither ClpX variant binds ATP, hexamerizes or promotes the ClpXP-dependent degradation of either Phd or λO. However, in contrast to ClpX(T126A), the ClpX(K125T) mutant protein exhibits stable binding to Phd protein. These results show that both Phd degradation and its binding to the ClpX chaperone can be important in the modulation of the levels of active Doc toxin. The regulation of the heat shock sigma factor σ32 and of the general stress response sigma factor σS are the best-studied examples for a key role of proteolysis in the control of stress responses. Both σ32 and σS are synthesized but are extremely unstable under non-stress conditions (because they are degraded by FtsH and RssB/ClpXP respectively), and can be stabilized instantaneously in response to various stresses. This allows an extraordinarily rapid upregulation of these sigma factors. Whereas a single intracellular signal, i.e. an increase in denatured proteins and therefore titration of the DnaK chaperone system, is the key event in σ32 stabilization (Tomoyasu et al., 1998), multiple signals (i.e. starvation, osmotic or temperature upshift, pH downshift) have to be integrated in the control of σS proteolysis. This occurs (i) by controlling the phosphorylation state of the recognition factor RssB, (ii) by titration of RssB by suddenly increased rates of σS synthesis, as well as (iii) by affecting the competition of σS and σ70 for RNAP core enzyme, as σS within the holoenzyme is protected against proteolysis (Hengge-Aronis, 2002; Pruteanu and Hengge-Aronis, 2002). Control of σS proteolysis represents a complex switch mechanism. The off-state (low σS levels due to rapid degradation) is stabilized by a homeostatic feedback mechanism (σS controls RssB expression) that operates up to a certain threshold, where RssB levels are not further increased, which results in RssB titration and therefore a switch into the on-state (high levels of stable σS) (Mihaela Pruteanu from R. Hengge's laboratory, Freie Universität Berlin, Germany; initial mathematical modelling presented by Tobias Backfisch from E.D. Gilles’ group, Max Planck Institute Magdeburg, Germany). Dps, a σS-regulated nucleoid-associated DNA-protective protein that accumulates to substantial levels in cells exposed to starvation or oxidative stress, is a ClpXP substrate (Flynn et al., 2003). Dps degradation is differentially controlled by stress signals. Like σS, Dps is stabilized by starvation but, in contrast to σS degradation, Dps proteolysis is inhibited by oxidative stress (but not by hyperosmotic shift), and is not dependent on RssB (Kunigunde Stephani from R. Hengge's laboratory, Freie Universität Berlin, Germany). Flagellum biosynthesis is a highly regulated process, which in enteric bacteria integrates signals that reflect nutritional conditions. The master regulator of the flagellar regulatory cascade is the FlhC/D complex, which has turned out to be a ClpXP substrate (Tomoyasu et al., 2002). Interestingly, the FlhC/D complex as well as FlhD alone are degraded by ClpXP, whereas FlhC alone is stable, indicating a case of ‘trans’-recognition or exposure of a proteolytic determinant in FlhC only when bound to FlhD. The regulatory role of ClpXP-mediated turnover of FlhC/D is not yet clear (Toshifumi Tomoyasu, Chiba University, Japan). ftsH knockout strains of B. subtilis display a pleiotropic phenotype that includes sensitivity to salt and heat stress, defects in sporulation and competence and filamentous growth. Potential substrates for the FtsH protease were identified by comparing the proteomes of ftsH wild-type and ftsH knockout cells (Wolfgang Schumann, Universität Bayreuth, Germany). At least four identified and five unidentified proteins were present in increased amounts in the absence of the protease. One of them, Pbp4*, is a member of the σW regulon and FtsH was found to control its transcription (and that of several other genes of this regulon). σW is an ECF sigma factor that controls genes involved in coping with disturbed cell wall biosynthesis (Cao et al., 2002). Formally, the FtsH protease acts as a repressor of the basal level of σW activity, suggesting that σW might be a FtsH substrate and that the expression of the σW regulon could be subject to differential proteolytic control (Zellmeier et al., 2003). In Corynebacterium glutamicum, ClpCP was observed to be indirectly autoregulated (Steffen Schaffer, Forschungszentrum Jülich, Germany). This control involves a regulatory protein, designated ClgR (for clp gene regulator), which is required for activation of clpC and clpP1P2 transcription. As the otherwise highly unstable ClgR is stabilized both in the clpC and a conditional clpP1P2 mutant, it is proposed that clpC and clpP expression in C. glutamicum is controlled via conditional degradation of ClgR by the Clp protease. Increased levels of denatured proteins, i.e. ClpCP substrates, may thus result in upregulation of ClpCP. This mechanism seems to be widely conserved, as C" @default.
• W1569886462 created "2016-06-24" @default.
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• W1569886462 date "2003-09-01" @default.
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• W1569886462 title "Proteolysis in prokaryotes: protein quality control and regulatory principles" @default.
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• W1569886462 doi "https://doi.org/10.1046/j.1365-2958.2003.03693.x" @default.
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