Chapter 27 : Intercellular Signaling by Rhomboids in Eukaryotes and Prokaryotes

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Intercellular Signaling by Rhomboids in Eukaryotes and Prokaryotes, Page 1 of 2

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The rhomboid family of intramembrane serine proteases controls a variety of functions in both eukaryotes and prokaryotes. The rhomboid proteins were originally identified in where they are required for growth factor signal generation. However, in recent years, a number of diverse functions for the rhomboid proteins have been identified. These functions include (i) the cleavage of TatA, a membrane-bound component of the twin arginine transport system that is required for cell-cell signaling in a prokaryote; (ii) regulating mitochondrial membrane fusion in and (iii) cleavage of cell surface adhesions in apicomplexan parasites. Recent biochemical analyses combined with crystallography studies have confirmed these enzymes use a Ser-His catalytic dyad. Moreover, the active-site serine of these enzymes is embedded within the membrane bilayer, and access to water in the membrane is mediated by a hydrophilic cavity that extends from the extracellular environment to the active-site serine. This chapter expands on each of the above themes and provides some future directions for the analysis of this novel class of membrane proteases.

Citation: Freeman M, Rather P. 2008. Intercellular Signaling by Rhomboids in Eukaryotes and Prokaryotes, p 431-442. In Winans S, Bassler B (ed), Chemical Communication among Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815578.ch27

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Bacteria and Archaea
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Image of FIGURE 1

Rhomboid-1 has seven transmembrane domains, and its active site comprises residues within the plane of the lipid bilayer. It cleaves its substrate, Spitz, within the TMD. This allows the extracellular domain of Spitz to be released from the cell, so that it can activate the EGF receptor in neighboring cells. Catalytic and other key residues are shown.

Citation: Freeman M, Rather P. 2008. Intercellular Signaling by Rhomboids in Eukaryotes and Prokaryotes, p 431-442. In Winans S, Bassler B (ed), Chemical Communication among Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815578.ch27
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Image of FIGURE 2

Alignment of the N-terminal region of TatA proteins from and The arrowhead designates the site of AarA-dependent cleavage for the TatA protein.

Citation: Freeman M, Rather P. 2008. Intercellular Signaling by Rhomboids in Eukaryotes and Prokaryotes, p 431-442. In Winans S, Bassler B (ed), Chemical Communication among Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815578.ch27
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1. Baker, R. P.,, R. Wijetilaka,, and S. Urban. 2006. Two Plasmodium rhomboid proteases preferentially cleave different adhesins implicated in all invasive stages of malaria. PLoS Pathog. 2:e113.
2. Bang, A. G.,, and C. Kintner. 2000. Rhomboid and Star facilitate presentation and processing of the Drosophila TGF-alpha homolog Spitz. Genes Dev. 14:177186.
3. Bate, M.,, and A. Martinez-Arias. 1993. The Development of Drosophila melanogaster. Cold Spring Harbor Laboratory Press, Plainview, NY.
4. Ben-Shem, A.,, D. Fass,, and E. Bibi. 2006. Structural basis for intramembrane proteolysis by rhomboid serine proteases. Proc. Natl. Acad. Sci USA 104:462466.
5. Bernhardt, T. G.,, and P. A. J. de Boer. 2003. The Escherichia coli amidase AmiC is a periplasmic septal ring component exported via the twin-arginine transport pathway. Mol. Microbiol. 48:11711182.
6. Bier, E.,, L. Y. Jan,, and Y. N. Jan. 1990. Rhomboid, a gene required for dorsoventral axis establishment and peripheral nervous system development in Drosophila melanogaster. Genes Dev. 4:190203.
7. Bolhuis, A.,, E. G. Bogsch,, and C. Robinson. 2000. Subunit interactions in the twin arginine translocase complex of Escherichia coli. FEBS Lett. 472:8892.
8. Brossier, F.,, T. J. Jewett,, L. D. Sibley,, and S. Urban. 2005. A spatially localized rhomboid pro-tease cleaves cell surface adhesins essential for invasion by Toxoplasma. Proc. Natl. Acad. Sci. USA 102:41464151.
9. Clemmer, K. M.,, G. M. Sturgill,, A. Veenstra,, and P. N. Rather. 2006. Functional characterization of Escherichia coli GlpG and additional rhomboid proteins using an aarA mutant of Providencia stuartii. J. Bacteriol. 188:34153419.
10. de Leeuw, E.,, T. Granjon,, I. Porcelli,, M. Alami,, S. B. Carr,, M. Mueller,, F. Sargent,, T. Palmer,, and B. C. Berks. 2002. Oligomeric properties and signal peptide binding by Escherichia coli Tat protein transport complexes. J. Mol. Biol. 322:11351146.
11. Del Rio, A.,, K. Dutta,, J. Chavez,, I. Ubarretxena-Belandia,, and R. Ghose. 2006. Solution structure and dynamics of the N-terminal cytosolic domain of rhomboid intramembrane protease from Pseudomonas aeruginosa: insights into a functional role in intramembrane proteolysis. J. Mol. Biol. 365:109122.
12. De Strooper, B.,, W. Annaert,, P. Cupers,, P. Saftig,, K. Craessaerts,, J. S. Mumm,, E. H. Schroeter,, V. Schrijvers,, M. S. Wolfe,, W. J. Ray,, A. Goate,, and R. Kopan. 1999. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398:518522.
13. Dowse, T. J.,, J. C. Pascall,, K. D. Brown,, and D. Soldati. 2005. Apicomplexan rhomboids have a potential role in microneme protein cleavage during host cell invasion. Int. J. Parasitol. 35:747756.
14. Dutt, A.,, S. Canevascini,, E. Froehli-Hoier,, and A. Hajnal. 2004. EGF signal propagation during C. elegans vulval development mediated by ROM-1 rhomboid. PLoS Biol. 2:e334.
15. Freeman, M. 1994. The spitz gene is required for photoreceptor determination in the Drosophila eye where it interacts with the EGF receptor. Mech. Dev. 48:2533.
16. Freeman, M. 1997. Cell determination strategies in the Drosophila eye. Development 124:261270.
17. Gallio, M.,, and P. Kylsten. 2000. Providencia may help find a function for a novel widespread protein family. Curr. Biol. 10:693694.
18. Gallio, M.,, G. Sturgill,, P. N. Rather,, and P. Kylsten. 2002. A common mechanism for extracellular signaling in eukaryotes and prokaryotes. Proc. Natl. Acad Sci. USA 99:1220812213.
19. Gohlke, U.,, L. Pullan,, C. A. McDevitt,, I. Porcelli,, E. de Leeuw,, T. Palmer,, H. R. Saibil,, and B. C. Berks. 2005. The TatA component of the twin-arginine protein transport system forms channel complexes of variable diameter. Proc. Natl. Acad. Sci. USA 102:1048210486.
20. Golembo, M.,, E. Raz,, and B. Z. Shilo. 1996. The Drosophila embryonic midline is the site of Spitz processing, and induces activation of the EGF receptor in the ventral ectoderm. Development 122:33633370.
21. Guichard, A.,, B. Biehs,, M. A. Sturtevant,, L. Wickline,, J. Chacko,, K. Howard,, and E. Bier. 1999. rhomboid and Star interact synergistically to promote EGFR/MAPK signaling during Drosophila wing vein development. Development 126:26632676.
22. Heidrich, C.,, M. F. Templin,, A. Ursinus,, M. Merdanovic,, J. Berger,, H. Schwarz,, M. A. de Pedro,, and J. V. Höltje. 2001. Involvement of N-acetylmuramyl-l-alanine amidases in cell separation and antibiotic-induced autolysis of Escherichia coli. Mol. Microbiol. 41:167178.
23. Heidrich C.,, A. Ursinus,, J. Berger,, H. Schwarz,, and J. V. Holtje. 2002. Effects of multiple deletions of murein hydrolases on viability, septum cleavage, and sensitivity to large toxic molecules in Escherichia coli. J. Bacteriol. 184:60936099.
24. Herlan, M.,, C. Bornhovd,, K. Hell,, W. Neupert,, and A. S. Reichert. 2004. Alternative topogenesis of Mgm1 and mitochondrial morphology depend on ATP and a functional import motor. J. Cell. Biol. 165:167173.
25. Herlan, M.,, F. Vogel,, C. Bornhovd,, W. Neupert,, and A. S. Reichert. 2003. Processing of Mgm1 by the rhomboid-type protease Pcp1 is required for maintenance of mitochondrial morphology and of mitochondrial DNA. J. Biol. Chem. 278:2778127788.
26. Howell, S. A.,, F. Hackett,, A. M. Jongco,, C. Withers-Martinez,, K. Kim,, V. B. Carruthers,, and M. J. Blackman. 2005. Distinct mechanisms govern proteolytic shedding of a key invasion protein in apicomplexan pathogens. Mol. Microbiol. 57:13421356.
27. Ize, B.,, N. R. Stanley,, G. Buchanan,, and T. Palmer. 2003. Role of the Escherichia coli Tat pathway in outer membrane integrity. Mol. Microbiol. 48:11831193.
28. Koonin, E. V.,, K. S. Makarova,, I. B. Rogozin,, L. Davidovic,, M. C. Letellier,, and L. Pellegrini. 2003. The rhomboids:a nearly ubiquitous family of intramembrane serine proteases that probably evolved by multiple ancient horizontal gene transfers. Genome Biol. 4:R19.
29. Lazarov, V. K.,, P. C. Fraering,, W. Ye,, M. S. Wolfe,, D. J. Selkoe,, and H. Li. 2006. Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores. Proc. Natl. Acad. Sci. USA 103:68896894.
30. Lee, J. R.,, S. Urban,, C. F. Garvey,, and M. Freeman. 2001. Regulated intracellular ligand transport and proteolysis control EGF signal activation in Drosophila. Cell 107:161171.
31. Lemberg, M. K.,, and M. Freeman. 2007. Functional and evolutionary implications of enhanced genomic analysis of rhomboid intramembrane proteases, Genome Res. 17:16341646.
32. Lemberg, M. K.,, J. Menendez,, A. Misik,, M. Garcia,, C. M. Koth,, and M. Freeman. 2005. Mechanism of intramembrane proteolysis investigated with purified rhomboid proteases. EMBO J. 24:464472.
33. Maegawa, S.,, K. Ito,, and Y. Akiyama. 2005. Proteolytic action of GlpG, a rhomboid protease in the Escherichia coli cytoplasmic membrane. Biochemistry 44:1354313552.
34. Mayer, U.,, and C. Nüsslein-Volhard. 1988. A group of genes required for pattern formation in the ventral ectoderm of the Drosophila embryo. Genes Dev. 2:14961511.
35. McQuibban, G. A.,, S. Saurya,, and M. Freeman. 2003. Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature 423:537541.
36. O’Donnell, R. A.,, F. Hackett,, S. A. Howell,, M. Treeck,, N. Struck,, Z. Krnajski,, C. Withers-Martinez,, T. W. Gilberger,, and M. J. Blackman. 2006. Intramembrane proteolysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite. J. Cell Biol. 174:10231033.
37. Ogura, T.,, K. Mio,, I. Hayashi,, H. Miyashita,, R. Fukuda,, R. Kopan,, T. Kodama,, T. Hamakubo,, T. Iwatsubo,, T. Tomita,, and C. Sato. 2006. Three-dimensional structure of the gamma-secretase complex. Biochem. Biophys. Res. Commun. 343:525534.
38. Palmer, T.,, F. Sargent,, and B. C. Berks. 2005. Export of complex cofactor-containing proteins by the bacterial Tat pathway. Trends Microbiol. 13:175180.
39. Pascall, J. C.,, J. E. Luck,, and K. D. Brown. 2002. Expression in mammalian cell cultures reveals interdependent, but distinct, functions for Star and rhomboid proteins in the processing of the Drosophila transforming-growth-factor-alpha homologue Spitz. Biochem. J. 363:347352.
40. Payie, K. G.,, P. N. Rather,, and A. J. Clarke. 1995. Contribution of gentamicin 2′-N-acetyltransferase to the O-acetylation of peptidoglycan in Providencia stuartii. J. Bacteriol. 177:43034310.
41. Porcelli, I.,, E. de Leeuw,, R. Wallis,, E. van den Brink-van der Laan,, B. de Kruijff,, B. A. Wallace,, T. Palmer, and B. C. Berks. 2002. Characterization and membrane assembly of the TatA component of the Escherichia coli twin-arginine protein transport system. Biochemistry 41:1369013697.
42. Priyadarshini, R.,, D. L. Popham,, and K. D. Young. 2006. Daughter cell separation by penicillin-binding proteins and peptidoglycan amidases in Escherichia coli. J. Bacteriol. 188:53455355.
43. Rather, P. N.,, X. Ding,, R. R. Baca-DeLancey,, and S. Sidduqui. 1999. Providencia stuartii genes activated by cell-cell signaling and identification of a gene required for the production or activity of an extracellular factor. J. Bacteriol. 181:71857191.
44. Rather, P. N.,, and D. R. Macinga. 1999. The chromosomal 2′-N-acetyltransferase of Providencia stuartii: physiological functions and genetic regulation. Front. Biosci. 4:132140.
45. Rather, P. N.,, and E. Orosz. 1994. Characterization of aarA, a pleiotrophic negative regulator of the 2′-N-acetyltransferase in Providencia stuartii. J. Bacteriol. 176:51405144.
46. Rather, P. N.,, E. Orosz,, R. Hare,, G. Miller,, and K. Shaw. 1993. Characterization and transcriptional regulation of the 2′-N-acetyltransferase gene of Providencia stuartii. J. Bacteriol. 175:64926498.
47. Rather, P. N.,, M. M. Parojcic,, and M. R. Paradise. 1997. An extracellular factor regulating expression of the chromosomal aminoglycoside 2′-N-acetyltransferase in Providencia stuartii. Antimicrob. Agents Chemother. 41:17491754.
48. Rawson, R. B.,, N. G. Zelenski,, D. Nijhawan,, J. Ye,, J. Sakai,, M. T. Hasan,, T. Y. Chang,, M. S. Brown,, and J. L. Goldstein. 1997. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Mol. Cell. 1:4757.
49. Ruohola-Baker, H.,, E. Grell,, T. B. Chou,, D. Baker,, L. Y. Jan,, and Y. N. Jan. 1993. Spatially localized rhomboid is required for establishment of the dorsal-ventral axis in Drosophila oogenesis. Cell 73:953965.
50. Santini, C. L.,, B. Ize,, A. Chanal,, M. Muller,, G. Giordano,, and L. F. Wu. 1998. A novel sec-independent periplasmic protein translocation pathway in Escherichia coli. EMBO J. 17:101112.
51. Sargent, F.,, E. G. Bogsch,, N. R. Stanley,, M. Wexler,, C. Robinson,, B. C. Berks,, and T. Palmer. 1998. Overlapping functions of components of a bacterial Sec-independent protein export pathway. EMBO J. 17:36403650.
52. Sargent, F.,, U. Gohlke,, E. de Leeuw,, N. R. Stanley,, T. Palmer,, H. R. Saibil,, and B. C. Berks. 2001. Purified components of the Escherichia coli Tat protein transport system form a double layered ring structure. Eur. J. Biochem. 268:33613367.
53. Shilo, B. Z. 2003. Signaling by the Drosophila epidermal growth factor receptor pathway during development. Exp. Cell. Res. 284:140149.
54. Stanley, N. R.,, K. Findlay,, B. C. Berks,, and T. Palmer. 2001. Escherichia coli strains blocked in Tat-dependent protein export exhibit pleiotrophic defects in the cell envelope. J. Bacteriol. 183:139144.
55. Stevenson, L. G.,, K. Strisovsky,, K. M. Clemmer,, S. Bhatt,, M. Freeman,, and P. N. Rather. 2007. The rhomboid protease AarA mediates quorum sensing in Providencia stuartii by activating TatA of the twin arginine translocase. Proc. Natl. Acad. Sci USA 104:10031008.
56. Sturtevant, M. A.,, M. Roark,, and E. Bier. 1993. The Drosophila rhomboid gene mediates the localized formation of wing veins and interacts genetically with components of the EGF-R signaling pathway. Genes Dev. 7:961973.
57. Tolia, A.,, L. Chavez-Gutierrez,, and B. De Strooper. 2006. Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the gamma-secretase complex. J. Biol. Chem. 281:2763327642.
58. Tsruya, R.,, A. Schlesinger,, A. Reich,, L. Gabay,, A. Sapir,, and B. Z. Shilo. 2002. Intracellular trafficking by Star regulates cleavage of the Drosophila EGF receptor ligand Spitz. Genes Dev. 16:222234.
59. Urban, S.,, and M. Freeman. 2003. Substrate specificity of rhomboid intramembrane proteases is governed by helix-breaking residues in the substrate transmembrane domain. Mol. Cell 11:14251434.
60. Urban, S.,, and M. Freeman. 2002. Intramembrane proteolysis controls diverse signaling pathways throughout evolution. Curr. Opin. Genet. Dev. 12:512518.
61. Urban, S.,, J. R. Lee,, and M. Freeman. 2001. Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107:173182.
62. Urban, S.,, D. Schlieper,, and M. Freeman. 2002. Conservation of intramembrane proteolytic activity and substrate specificity in prokaryotic and eukaryotic rhomboids. Curr. Biol. 12:15071512.
63. Urban, S.,, and M. S. Wolfe. 2005. Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity. Proc. Natl. Acad. Sci. USA 102:18831888.
64. Wang, Y.,, Y. Zhang,, and Y. Ha. 2006. Crystal structure of a rhomboid family intramembrane protease. Nature 444:179180.
65. Wasserman, J. D.,, S. Urban,, and M. Freeman. 2000. A family of rhomboid-like genes: Drosophila rhomboid-1 and roughoid/rhomboid-3 cooperate to activate EGF receptor signalling. Genes Dev. 14:16511663.
66. Weihofen, A.,, K. Binns,, M. K. Lemberg,, K. Ashman,, and B. Martoglio. 2002. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296:22152218.
67. Weiner, J. H.,, P. T. Bilous,, G. M. Shaw,, S. P. Lubitz,, L. Frost,, G. H. Thomas,, J. A. Cole,, and R. J. Turner. 1998 A novel and ubiquitous system for membrane targeting and secretion of cofactor containing proteins. Cell. 93:93101.
68. Wexler, M.,, F. Sargent,, R. L. Jack,, N. R. Stanley,, E. G. Bogsch,, C. Robinson,, B. C. Berks,, and T. Palmer. 2000. TatD is a cytoplasmic protein with DNase activity. No requirement for TatD family proteins in sec-independent protein export. J. Biol. Chem. 275:1671716722.
69. Wolfe, M. S.,, and R. Kopan. 2004. Intramembrane proteolysis: theme and variations. Science 305:11191123.
70. Wolfe, M. S.,, W. Xia,, B. L. Ostaszewski,, T. S. Diehl,, W. T. Kimberly,, and D. J. Selkoe. 1999. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398:513517.
71. Wu, Z.,, N. Yan,, L. Feng,, A. Oberstein,, H. Yan,, R. P. Baker,, L. Gu,, P. D. Jeffrey,, S. Urban,, and Y. Shi. 2006. Structural analysis of a rhomboid family intramembrane protease reveals a gating mechanism for substrate entry. Nat. Struct. Mol. Biol. 13:10841091.

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