A conserved mechanism for extracellular signaling in eukaryotes and prokaryotes

Gallio, Marco; Sturgill, Gwen M.; Rather, Philip N.; Kylsten, Per

doi:10.1073/pnas.192138799

Cited by 108 publications

(78 citation statements)

References 31 publications

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“…In the bacterium Providencia stuartii, cleavage of a small inhibitory N-terminal peptide from the twin-arginine translocase TatA by the rhomboid protease AarA initiates quorum sensing by activating TatA's function as a channel for export of the quorumsensing signal [30,31]. Interestingly, most bacteria do not encode a TatA protein with an N-terminal extension and therefore do not have to be activated by cleavage, suggesting that the role of AarA is a rare adaptation rather than a general mechanism (reviewed in [32]).…”

Section: Role In Signallingmentioning

confidence: 99%

New insights into parasite rhomboid proteases

Santos

Graindorge

Soldati‐Favre

2012

Molecular and Biochemical Parasitology

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a b s t r a c tThe rhomboid-like proteins constitute a large family of intramembrane serine proteases that are present in all branches of life. First studied in Drosophila, these enzymes catalyse the release of the active forms of proteins from the membrane and hence trigger signalling events. In protozoan parasites, a limited number of rhomboid-like proteases have been investigated and some of them are associated to pathogenesis. In Apicomplexans, rhomboid-like protease activity is involved in shedding adhesins from the surface of the zoites during motility and host cell entry. Recently, a Toxoplasma gondii rhomboid was also implicated in an intracellular signalling mechanism leading to parasite proliferation. In Entamoeba histolytica, the capacity to adhere to host cells and to phagocytose cells is potentiated by a rhomboid-like protease. Survey of a small number of protozoan parasite genomes has uncovered species-specific rhomboidlike protease genes, many of which are predicted to encode inactive enzymes. Functional investigation of the rhomboid-like proteases in other protozoan parasites will likely uncover novel and unexpected implications for this family of proteases.

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Section: Role In Signallingmentioning

confidence: 99%

New insights into parasite rhomboid proteases

Santos

Graindorge

Soldati‐Favre

2012

Molecular and Biochemical Parasitology

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“…Despite significant sequence divergence, many rhomboid enzymes from both prokaryotes and eukaryotes share biochemical characteristics (14,15). The first rhomboid enzyme was discovered in Drosophila and functions in cleaving transmembrane epidermal growth factor ligands including Spitz to initiate signaling, but bacterial forms also can cleave Spitz (15,16). Mechanistic analyses revealed that Spitz is recognized by diverse rhomboid enzymes through the upper seven residues of its transmembrane domain, termed the Spitz substrate motif (14).…”

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confidence: 99%

Enzymatic analysis of a rhomboid intramembrane protease implicates transmembrane helix 5 as the lateral substrate gate

Baker

Young

Feng

et al. 2007

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

132

221

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Intramembrane proteolysis is a core regulatory mechanism of cells that raises a biochemical paradox of how hydrolysis of peptide bonds is accomplished within the normally hydrophobic environment of the membrane. Recent high-resolution crystal structures have revealed that rhomboid proteases contain a catalytic serine recessed into the plane of the membrane, within a hydrophilic cavity that opens to the extracellular face, but protected laterally from membrane lipids by a ring of transmembrane segments. This architecture poses questions about how substrates enter the internal active site laterally from membrane lipid. Because structures are static glimpses of a dynamic enzyme, we have taken a structure-function approach analyzing >40 engineered variants to identify the gating mechanism used by rhomboid proteases. Importantly, our analyses were conducted with a substrate that we show is cleaved at two intramembrane sites within the previously defined Spitz substrate motif. Engineered mutants in the L1 loop and active-site region of the GlpG rhomboid protease suggest an important structural, rather than dynamic, gating function for the L1 loop that was first proposed to be the substrate gate. Conversely, three classes of mutations that promote transmembrane helix 5 displacement away from the protease core dramatically enhanced enzyme activity 4-to 10-fold. Our functional analyses have identified transmembrane helix 5 movement to gate lateral substrate entry as a rate-limiting step in intramembrane proteolysis. Moreover, our mutagenesis also underscores the importance of other residue interactions within the enzyme that warrant further scrutiny.cell signaling ͉ presenilin ͉ signal peptide peptidase ͉ site-2 protease

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“…In Drosophila, rhomboid proteins cleave the transmembrane domain of the epidermal growth factor receptor ligands, thereby releasing them to activate signaling (10). Drosophila Rhomboid-1 and AarA are able to functionally substitute for each other, indicating that the specificity of these rhomboids has been conserved across evolution (11). However, despite these similarities, the physiological substrate of AarA and the mechanism mediating AarA-dependent quorum-sensing in Prov.…”

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confidence: 99%

Rhomboid protease AarA mediates quorum-sensing in Providencia stuartii by activating TatA of the twin-arginine translocase

Stevenson

Střı́šovský

Clemmer

et al. 2007

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

146

139

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The Providencia stuartii AarA protein is a member of the rhomboid family of intramembrane serine proteases and is required for the production of an unknown quorum-sensing molecule. In a screen to identify rhomboid-encoding genes from Proteus mirabilis, tatA was identified as a multicopy suppressor and restored extracellular signal production as well as complementing all other phenotypes of a Prov. stuartii aarA mutant. TatA is a component of the twin-arginine translocase (Tat) protein secretion pathway and likely forms a secretion pore. By contrast, the native tatA gene of Prov. stuartii in multicopy did not suppress an aarA mutation. We find that TatA in Prov. stuartii has a short N-terminal extension that was atypical of TatA proteins from most other bacteria. This extension was proteolytically removed by AarA both in vivo and in vitro. A Prov. stuartii TatA protein missing the first 7 aa restored the ability to rescue the aarA-dependent phenotypes. To verify that loss of the Tat system was responsible for the various phenotypes exhibited by an aarA mutant, a tatC-null allele was constructed. The tatC mutant exhibited the same phenotypes as an aarA mutant and was epistatic to aarA. These data provide a molecular explanation for the requirement of AarA in quorum-sensing and uncover a function for the Tat protein export system in the production of secreted signaling molecules. Finally, TatA represents a validated natural substrate for a prokaryotic rhomboid protease.

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A conserved mechanism for extracellular signaling in eukaryotes and prokaryotes

Cited by 108 publications

References 31 publications

New insights into parasite rhomboid proteases

New insights into parasite rhomboid proteases

Enzymatic analysis of a rhomboid intramembrane protease implicates transmembrane helix 5 as the lateral substrate gate

Rhomboid protease AarA mediates quorum-sensing in Providencia stuartii by activating TatA of the twin-arginine translocase

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