Mutational Analysis of Potential Zinc-Binding Residues in the Active Site of the Enterococcal <scp>d</scp>-Ala-<scp>d</scp>-Ala Dipeptidase VanX

McCafferty, Dewey G.; Lessard, Ivan A. D.; Walsh, Christopher T.

doi:10.1021/bi970543u

Cited by 97 publications

(106 citation statements)

References 30 publications

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“…RpoS is required for the recovery of the D-Ala-D-Ala dipeptide because it controls the expression of both the peptidase and the transport system (39). Control over the expression of cell wall remodeling enzymes is critical for cell integrity (40)(41)(42). Finally, the increased synthesis of MS channels upon entry into stationary phase may represent a component of the coordinated modification of the cytoplasmic membrane.…”

Section: Discussionmentioning

confidence: 99%

A role for mechanosensitive channels in survival of stationary phase: Regulation of channel expression by RpoS

Stokes

Murray

Subramaniam

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

111

101

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The mechanosensitive (MS) channels MscS and MscL are essential for the survival of hypoosmotic shock by Escherichia coli cells. We demonstrate that MscS and MscL are induced by osmotic stress and by entry into stationary phase. Reduced levels of MS proteins and reduced expression of mscL-and mscS-LacZ fusions in an rpoS mutant strain suggested that the RNA polymerase holoenzyme containing S is responsible, at least in part, for regulating production of MS channel proteins. Consistent with the model that the effect of S is direct, the MscS and MscL promoters both use RNA polymerase containing S in vitro. Conversely, clpP or rssB mutations, which cause enhanced levels of S , show increased MS channel protein synthesis. RpoS null mutants are sensitive to hypoosmotic shock upon entry into stationary phase. These data suggest that MscS and MscL are components of the RpoS regulon and play an important role in ensuring structural integrity in stationary phase bacteria.

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Section: Discussionmentioning

confidence: 99%

A role for mechanosensitive channels in survival of stationary phase: Regulation of channel expression by RpoS

Stokes

Murray

Subramaniam

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

111

101

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“…Expression of Biotinylated Recombinant Proteins-AviTag, a specific peptide sequence that can be biotinylated with biotin ligase, was cloned into a pIAD16 vector (18) to generate a pIAD16Avi plasmid. APP fragments with FLAG tag were inserted into the pIAD16Avi vector.…”

Section: Methodsmentioning

confidence: 99%

Dual Role of α-Secretase Cleavage in the Regulation of γ-Secretase Activity for Amyloid Production

Tian

Crump

2010

Journal of Biological Chemistry

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Processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases generates pathogenic ␤-amyloid (A␤) peptides associated with Alzheimer disease (AD), whereas cleavage of APP by ␣-secretases precludes A␤ formation. Little is known about the role of ␣-secretase cleavage in ␥-secretase regulation. Here, we show that ␣-secretase-cleaved APP C-terminal product (␣CTF) functions as an inhibitor of ␥-secretase. We demonstrate that the substrate inhibitory domain (ASID) within ␣CTF, which is bisected by the ␣-secretase cleavage site, contributes to this negative regulation because deleting or masking this domain turns ␣CTF into a better substrate for ␥-secretase. Moreover, ␣-secretase cleavage can potentiate the inhibitory effect of ASID. Inhibition of ␥-secretase activity by ␣CTF is observed in both in vitro and cellular systems. This work reveals an unforeseen role for ␣-secretase in generating an endogenous ␥-secretase inhibitor that down-regulates the production of A␤. Deregulation of this feedback mechanism may contribute to the pathogenesis of AD.The amyloid precursor protein (APP) 2 is sequentially cleaved by ␤-and ␥-secretases to generate A␤ peptides, which are widely considered to play a causative role in the pathogenesis of Alzheimer disease (AD) (1). This pathway also generates soluble APP␤ (sAPP␤) and APP intracellular domain. Alternatively, APP can be processed by ␣-secretase that cuts within A␤ peptides, which precludes the formation of toxic peptides. Similarly, the ␣/␥ pathway leads to formation of soluble APP␣ (sAPP␣), the P3 peptide, and the APP intracellular domain. It appears that ␥-secretase cleavage of substrates first requires another protease that removes the majority of the extracellular domain of the substrate. The sequential cleavage of APP is characteristic of regulated intramembrane proteolysis (RIP) (2). RIP generally requires two proteolytic steps, whereby the second intramembrane cleavage is dependent on the first cleavage, such as in Notch and sterol regulatory element binding proteins signaling. RIP has been found to govern sterol regulation, cell fate determination, unfolded protein responses, growth factor activation, mitochondria membrane remodeling, and apoptosis (2-5).A distinctive feature of APP processing compared with other RIPs is the existence of two proteases (␤-and ␣-secretase) that are both capable of executing the first cleavage. Recent studies have shown that ␤-secretase cleavage removes the large extracellular domain of APP, freeing the N terminus of ␤CTF, which is recognized by nicastrin (6). Recruiting ␤CTF to the docking site makes the substrate accessible to the active site of ␥-secretase for hydrolysis. However, the role of nicastrin for substrate binding has been controversial (7-9). Nevertheless, ␤-secretase cleavage converts a latent substrate of ␥-secretase into an active one. Whether ␣-secretase plays a role similar to that of ␤-secretase in the regulation of APP processing by ␥-secretase is unknown. It has been suggested that ␣-secretase competes with ␤-...

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“…The crystal structure of ShhN was determined 15 years ago (Hall et al 1995), and revealed an unanticipated homology with zinc hydrolases ( Fig. 2A,B; Dideberg et al 1982;McCafferty et al 1997;Bochtler et al 2004). In ShhN and related zinc hydrolases, a zinc ion is coordinated by two histidines and an aspartate at the base of a large cleft.…”

Section: Hh Structurementioning

confidence: 99%

Interactions between Hedgehog proteins and their binding partners come into view

Beachy¹,

Hymowitz²,

Lazarus³

et al. 2010

Genes Dev.

190

158

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Hedgehog (Hh) proteins are secreted signaling molecules that mediate essential tissue-patterning events during embryonic development and function in tissue homeostasis and regeneration throughout life. Hh signaling is regulated by multiple mechanisms, including covalent lipid modification of the Hh protein and interactions with multiple protein and glycan partners. Unraveling the nature and effects of these interactions has proven challenging, but recent structural and biophysical studies of Hh proteins and active fragments of heparin, Ihog, Cdo, Boc, Hedgehog-interacting protein (Hhip), Patched (Ptc), and the monoclonal antibody 5E1 have added a new level of molecular detail to our understanding of how Hh signal response and distribution are regulated within tissues. We review these results and discuss their implications for understanding Hh signaling in normal and disease states.

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Mutational Analysis of Potential Zinc-Binding Residues in the Active Site of the Enterococcal d-Ala-d-Ala Dipeptidase VanX

Cited by 97 publications

References 30 publications

A role for mechanosensitive channels in survival of stationary phase: Regulation of channel expression by RpoS

A role for mechanosensitive channels in survival of stationary phase: Regulation of channel expression by RpoS

Dual Role of α-Secretase Cleavage in the Regulation of γ-Secretase Activity for Amyloid Production

Interactions between Hedgehog proteins and their binding partners come into view

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