Structure of a Site-2 Protease Family Intramembrane Metalloprotease

Feng, Liang; Yan, Hu; Wu, Zhuoru; Yan, Nieng; Wang, Zhe; Jeffrey, Philip D.; Shi, Yigong

doi:10.1126/science.1150755

Cited by 214 publications

(259 citation statements)

References 31 publications

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“…Topological studies suggested that the active site was at or within the plane of the bilayer (Zelenski et al 1999). This inference is supported by recent crystal structure analysis of a bacterial S2P homolog (Feng et al 2007).…”

Section: Site-2 Protease (S2p)supporting

confidence: 64%

Intriguing parasites and intramembrane proteases: Figure 1.

Rawson

2008

Genes Dev.

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Rhomboid intramembrane proteases occur throughout the kingdoms of life. In this issue of Genes & Development, Baxt and colleagues (pp. 1636-1646) report that the single proteolytic rhomboid (EhROM1) from Entamoeba histolytica cleaves cell surface galactose-binding or N-acetylgalactosamine-binding (Gal/Gal-NAc) lectins. EhROM1 and lectins colocalize during phagocytosis and receptor capping. EhROM1 is found at the base of the cap rather than in the cap proper, suggesting a role in receptor shedding and implying that EhROM1 is crucial for amoebal infection.Parasitic protists are fascinating organisms in their own right, with their typically complex life cycles, distinctive physiologies, and uncertain relationships. They are of immense practical interest as well; parasitic infections account for an enormous proportion of the disease burden on the human population worldwide. The debilitating and often lethal parasitic diseases remain among the most intractable infections and result in between 1.5 and 3 million deaths annually. The enormous costs resulting from lost productivity and caring for the millions who suffer from parasitic disease represent significant hurdles to economic development throughout the world, and these burdens tend to be the highest where the resources to bear them are the least. Advances in our understanding of parasites, such as how they initiate and maintain infections, therefore, have significant potential to improve human health and well-being worldwide.Among parasitic diseases, amoebiasis ranks second only to malaria in global morbidity, affecting vast numbers of people worldwide and killing some 100,000 annually (World Health Organization 1997). The causative agent of human amoebiasis, Entamoeba histolytica, faces many of the same challenges faced by other parasites when establishing infection. Baxt et al. (2008) detail the role of the single rhomboid intramembrane protease from E. histolytica in crucial parasite processes: phagocytosis and immune evasion. The parasitic lifestyleParasitism poses common challenges to the diverse organisms that practice it. Parasites must first locate and enter a host. Next, in many cases, host tissues or cells must be invaded, requiring some means of attachment and introgression. The successful parasite usually establishes a long-term infection, and this potentially affords the host ample time to mount a vigorous immune response to the invader. In order to survive and reproduce while "dining at another's table," the parasite must somehow manage to evade host immune defenses that may act at several stages of the infection cycle. Broadly, extracellular parasites are subject to the humoral response, while intracellular stages are the target of cellular immunity. Invasion and evasionStrategies for evading the host immune response are as complex and varied as the parasites that use them, and most parasites use several different strategies in the course of infection. Parasites may engage various responses to the host immune system (Zambrano-Villa et al. 2002). So...

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Section: Site-2 Protease (S2p)supporting

confidence: 64%

Intriguing parasites and intramembrane proteases: Figure 1.

Rawson

2008

Genes Dev.

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“…In these ways, removal of the periplasmic domain transforms RseA into a substrate of RseP. In the case of presecretory proteins, removal of the large mature domains by Lep might facilitate effective access of SPs to the recessed intramembrane active site of RseP (29). This regulation might also require elements in the enzyme RseP itself.…”

Section: Discussionmentioning

confidence: 99%

Post-liberation cleavage of signal peptides is catalyzed by the site-2 protease (S2P) in bacteria

Saito

Hizukuri

Matsuo

et al. 2011

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

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A signal peptide (SP) is cleaved off from presecretory proteins by signal peptidase during or immediately after insertion into the membrane. In metazoan cells, the cleaved SP then receives proteolysis by signal peptide peptidase, an intramembrane-cleaving protease (I-CLiP). However, bacteria lack any signal peptide peptidase member I-CLiP, and little is known about the metabolic fate of bacterial SPs. Here we show that Escherichia coli RseP, an site-2 protease (S2P) family I-CLiP, introduces a cleavage into SPs after their signal peptidase-mediated liberation from preproteins. A Bacillus subtilis S2P protease, RasP, is also shown to be involved in SP cleavage. These results uncover a physiological role of bacterial S2P proteases and update the basic knowledge about the fate of signal peptides in bacterial cells. SPP belongs to intramembrane-cleaving proteases (I-CLiPs), which are classified into SPP/γ-secretase (aspartyl proteases), rhomboid (serine protease), and S2P (zinc metalloprotease) (5, 6). These proteases liberate otherwise membrane-tethered domains of membrane proteins to function as a regulatory molecule. I-CLiPs have specific intramolecular routes that make water molecules accessible to the intramembrane proteolytic active sites (5, 6). For such proteolysis to occur, γ-secretase/SPP and S2P require, in most cases, removal of the ectodomain of the substrate by other protease (5, 7). SPP and S2P prefer substrate with the type II transmembrane orientation and γ-secretase and rhomboid prefer the type I orientation (7).Bacteria contain S2Ps and rhomboids but not SPPs, and only limited knowledge is available about the fate of bacterial SPs (7). We and others have been characterizing RseP, an Escherichia coli member of the S2P involved in the σ E pathway extracytoplasmic stress response (8, 9). In this regulation, a protease, DegS, responds to misassembled outer membrane proteins and introduces the first proteolytic cleavage into RseA, a membraneintegrated anti-σ E protein (10). Subsequently, RseP introduces the second cleavage into RseA, activating σ E to transcribe stressinducible genes (8, 9). Although RseA is the only physiological substrate of RseP so far established, we have shown previously that RseP can cleave a wider range of transmembrane sequences having helix-destabilizing residues (11). Our preliminary results that RseP cleaved a β-lactamase (Bla) fusion protein at or around its SP (11), together with the fact that RseP and SPP share the substrate preference for the type II orientation, prompted us to undertake the present study. Our results suggest strongly that S2Ps (E. coli RseP and Bacillus subtilis RasP) are involved in degradation of remnant SPs left in the bacterial cytoplasmic membrane, in contrast with the currently prevailing concept that SppA (12, 13), a protease unrelated to the S2P or the SPP family, is the enzyme responsible for signal peptide cleavage in bacteria.

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“…1) (Rawson et al 1997;Feng et al 2007). Site-2 cleavage releases the NH 2 -terminal domains of the SREBPs from membranes, allowing them to enter the nucleus and activate transcription of their target genes (Fig.…”

Section: Regulation Of the Srebp Pathway In Cultured Cells Regulated mentioning

confidence: 99%