A novel clan of zinc metallopeptidases with possible intramembrane cleavage properties

Lewis, Alan P.; Thomas, P.J.

doi:10.1110/ps.8.2.439

Cited by 53 publications

(21 citation statements)

References 18 publications

(6 reference statements)

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“…SpoIVFB-S2P family members are intramembrane-acting, zinc metalloproteases and are found in a wide range of organisms, including many kinds of bacteria as well as flies and mammals (Lewis and Thomas 1999;Rudner et al 1999;Yu and Kroos 2000). In such systems, activation of the transcription factor is governed by two, successive proteolytic events known as Site-1 and Site-2 cleavage (Rawson et al 1997;Sakai et al 1998).…”

mentioning

confidence: 99%

Evidence for a novel protease governing regulated intramembrane proteolysis and resistance to antimicrobial peptides in Bacillus subtilis

Ellermeier¹,

Losick²

2006

Genes Dev.

121

161

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Evidence is presented that the activation of the RNA polymerase factor W in Bacillus subtilis by regulated intramembrane proteolysis is governed by a novel, membrane-embedded protease. The W factor is activated by proteolytic destruction of the membrane-bound anti-W factor RsiW in response to antimicrobial peptides and other agents that damage the cell envelope. RsiW is destroyed by successive proteolytic events known as Site-1 and Site-2 cleavage. Site-2 cleavage is mediated by a member of the SpoIVFB-S2P family of intramembrane-acting metalloproteases, but the protease responsible for Site-1 cleavage was unknown. We have identified a previously uncharacterized, multipass membrane protein called PrsW (annotated YpdC) that is both necessary and sufficient (when artificially produced in an unrelated host bacterium) for Site-1 cleavage of RsiW. PrsW is a member of a widespread family of membrane proteins that includes at least one previously known protease. We identify residues important for proteolysis and a cluster of acidic residues involved in sensing antimicrobial peptides and cell envelope stress.[Keywords: Signal transduction; Site-1 cleavage; ECF factor; antimicrobial peptides] Supplemental material is available at http://www.genesdev.org.

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mentioning

confidence: 99%

Evidence for a novel protease governing regulated intramembrane proteolysis and resistance to antimicrobial peptides in Bacillus subtilis

Ellermeier¹,

Losick²

2006

Genes Dev.

121

161

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“…Functions of the Ser-rich loop and the PDZ domain with its Cys-rich insert are unknown. The number of TMSs is uncertain but we favor the 8-TMS model proposed by Ha [19] in which TMSs 4, 5, and 6 form a conserved core predicted by sequence comparisons [2, 8]. A 3-TMS core was observed in the archaeal IMMP crystal structure [22].…”

Section: Membrane Topology and Extramembrane Domainsmentioning

confidence: 99%

“…Sequence analyses suggested that S2P is a polytopic membrane protein that is conserved in animals and archaea. Additional sequence comparisons identified similar proteins in the plant Arabidopsis thaliana and in diverse bacteria [2]. Shortly thereafter, mutational studies provided evidence that bacterial proteins SpoIVFB of Bacillus subtilis and YaeL (subsequently renamed RseP) of Escherichia coli are intramembrane metalloproteases (IMMPs) that cleave Pro-σ K and RseA, respectively [3–7].…”

Section: Introductionmentioning

confidence: 99%

Biochemical and structural insights into intramembrane metalloprotease mechanisms

Kroos

Akiyama

2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Intramembrane metalloproteases are nearly ubiquitous in living organisms and they function in diverse processes ranging from cholesterol homeostasis and the unfolded protein response in humans to sporulation, stress responses, and virulence of bacteria. Understanding how these enzymes function in membranes is a challenge of fundamental interest with potential applications if modulators can be devised. Progress is described toward a mechanistic understanding, based primarily on molecular genetic and biochemical studies of human S2P and bacterial SpoIVFB and RseP, and on the structure of the membrane domain of an archaeal enzyme. Conserved features of the enzymes appear to include transmembrane helices and loops around the active site zinc ion, which may be near the membrane surface. Extramembrane domains such as PDZ (PSD-95, DLG, ZO-1) or CBS (cystathionines-β-synthase) domains govern substrate access to the active site, but several different mechanisms of access and cleavage site selection can be envisioned, which might differ depending on the substrate and the enzyme. More work is needed to distinguish between these mechanisms, both for enzymes that have been relatively well-studied, and for enzymes lacking PDZ and CBS domains, which have not been studied.

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“…It is known that a catalytic glutamic acid (E) and two metal-coordinating histidines (H) in the HEXXH motif and a third metal-coordinating aspartic acid (D) in the N(X) 7 DG motif together form a zinc-binding site, which is the catalytic center of the S2Ps (38). It is thought that the glutamic acid activates a water molecule for cleaving an extended and therefore accessible TMH substrate peptide bond (48).…”

Section: Five Putative S2psmentioning

confidence: 99%

Identification and Characterization of Five Intramembrane Metalloproteases in Anabaena variabilis

Chen

Xiang

et al. 2012

J Bacteriol

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Regulated intramembrane proteolysis (RIP) involves cleavage of a transmembrane segment of a protein, releasing the active form of a membrane-anchored transcription factor (MTF) or a membrane-tethered signaling protein in response to an extracellular or intracellular signal. RIP is conserved from bacteria to humans and governs many important signaling pathways in both prokaryotes and eukaryotes. Proteases that carry out these cleavages are named intramembrane cleaving proteases (I-CLips). To date, little is known about I-CLips in cyanobacteria. In this study, five putative site-2 type I-Clips (Ava_1070, Ava_1730, Ava_1797, Ava_3438, and Ava_4785) were identified through a genome-wide survey in Anabaena variabilis. Biochemical analysis demonstrated that these five putative A. variabilis site-2 proteases (S2Ps Av ) have authentic protease activities toward an artificial substrate pro-K , a Bacillus subtilis MTF, in our reconstituted Escherichia coli system. The enzymatic activities of processing pro-K differ among these five S2Ps Av . Substitution of glutamic acid (E) by glutamine (Q) in the conserved HEXXH zinccoordinated motif caused the loss of protease activities in these five S2Ps Av , suggesting that they belonged to the metalloprotease family. Further mapping of the cleaved peptides of pro-K by Ava_4785 and Ava_1797 revealed that Ava_4785 and Ava_1797 recognized the same cleavage site in pro-K as SpoIVFB, a cognate S2P of pro-K from B. subtilis. Taking these results together, we report here for the first time the identification of five metallo-intramembrane cleaving proteases in Anabaena variabilis. The experimental system described herein should be applicable to studies of other RIP events and amenable to developing in vitro assays for I-CLips. Regulating the activity of transcription factors is an efficient way to regulate gene expression. In addition to several wellknown mechanisms for regulating the activity of transcription factors, such as posttranslational modifications (23, 27) and degradation of an antitranscription factor or its antagonistic protein (3, 15, 21), a recently discovered and little-understood regulation is intramembrane proteolysis of membrane-tethered transcription factors. Spatiotemporal sequestration of transcription factors in the cellular membrane is emerging as an elegant mechanism for the regulation of gene expression. The regulated intramembrane proteolysis (RIP) of membrane-tethered transcription factors (MTFs) (8,35,56) or membrane-anchored signaling proteins (MSPs) (12,57,59) by membrane-embedded proteases plays important roles in eliciting transcriptional responses in many vital cellular processes, including cell division and differentiation (6,12,48,51,66), cell migration (60), stress responses (3, 15, 26, 64), microbial pathogenesis (5, 40-42, 45), cholesterol biosynthesis (47), and human innate and adaptive immunity (20), as well as pathogenesis of cancer (4, 34, 39) and human diseases such as hyperlipidemias and Alzheimer's (51, 53). Since RIP-mediated signal transducti...

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A novel clan of zinc metallopeptidases with possible intramembrane cleavage properties

Cited by 53 publications

References 18 publications

Evidence for a novel protease governing regulated intramembrane proteolysis and resistance to antimicrobial peptides in Bacillus subtilis

Evidence for a novel protease governing regulated intramembrane proteolysis and resistance to antimicrobial peptides in Bacillus subtilis

Biochemical and structural insights into intramembrane metalloprotease mechanisms

Identification and Characterization of Five Intramembrane Metalloproteases in Anabaena variabilis

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