The tetratricopeptide repeat (TPR) structural motif is known to occur in a wide variety of proteins present in prokaryotic and eukaryotic organisms. The TPR motif represents an elegant module for the assembly of various multiprotein complexes, and thus, TPR-containing proteins often play roles in vital cell processes. As the TPR profile is well defined, the complete TPR protein repertoire of a bacterium with a known genomic sequence can be predicted. This provides a tremendous opportunity for investigators to identify new TPR-containing proteins and study them in detail. In the past decade, TPR-containing proteins of bacterial pathogens have been reported to be directly related to virulence-associated functions. In this minireview, we summarize the current knowledge of the TPR-containing proteins involved in virulence mechanisms of bacterial pathogens while highlighting the importance of TPR motifs for the proper functioning of class II chaperones of a type III secretion system in the pathogenesis of Yersinia, Pseudomonas, and Shigella.

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Kralove Charles University Prague Hradec Kralove Czech Republic

Zobrazit více v PubMed

Hirano T, Kinoshita N, Morikawa K, Yanagida M. 1990. Snap helix with knob and hole: essential repeats in S. pombe nuclear protein nuc2+. Cell 60:319–328 PubMed

Sikorski RS, Boguski MS, Goebl M, Hieter P. 1990. A repeating amino acid motif in CDC23 defines a family of proteins and a new relationship among genes required for mitosis and RNA synthesis. Cell 60:307–317 PubMed

Lamb JR, Tugendreich S, Hieter P. 1995. Tetratrico peptide repeat interactions: to TPR or not to TPR? Trends Biochem. Sci. 20:257–259 PubMed

D'Andrea LD, Regan L. 2003. TPR proteins: the versatile helix. Trends Biochem. Sci. 28:655–662 PubMed

Das AK, Cohen PW, Barford D. 1998. The structure of the tetratricopeptide repeats of protein phosphatase 5: implications for TPR-mediated protein-protein interactions. EMBO J. 17:1192–1199 PubMed PMC

Büttner CR, Sorg I, Cornelis GR, Heinz DW, Niemann HH. 2008. Structure of the Yersinia enterocolitica type III secretion translocator chaperone SycD. J. Mol. Biol. 375:997–1012 PubMed

Job V, Mattei PJ, Lemaire D, Attree I, Dessen A. 2010. Structural basis of chaperone recognition of type III secretion system minor translocator proteins. J. Biol. Chem. 285:23224–23232 PubMed PMC

Kim K, Oh J, Han D, Kim EE, Lee B, Kim Y. 2006. Crystal structure of PilF: functional implication in the type 4 pilus biogenesis in Pseudomonas aeruginosa. Biochem. Biophys. Res. Commun. 340:1028–1038 PubMed

Lunelli M, Lokareddy RK, Zychlinsky A, Kolbe M. 2009. IpaB-IpgC interaction defines binding motif for type III secretion translocator. Proc. Natl. Acad. Sci. U. S. A. 106:9661–9666 PubMed PMC

Grove TZ, Cortajarena AL, Regan L. 2008. Ligand binding by repeat proteins: natural and designed. Curr. Opin. Struct. Biol. 18:507–515 PubMed PMC

Blatch GL, Lassle M. 1999. The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. Bioessays 21:932–939 PubMed

Goodarzi MO, Xu N, Cui J, Guo X, Chen YI, Azziz R. 2008. Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA), a candidate gene for polycystic ovary syndrome. Hum. Reprod. 23:1214–1219 PubMed PMC

Sohocki MM, Bowne SJ, Sullivan LS, Blackshaw S, Cepko CL, Payne AM, Bhattacharya SS, Khaliq S, Qasim Mehdi S, Birch DG, Harrison WR, Elder FF, Heckenlively JR, Daiger SP. 2000. Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis. Nat. Genet. 24:79–83 PubMed PMC

Grizot S, Fieschi F, Dagher MC, Pebay-Peyroula E. 2001. The active N-terminal region of p67phox. Structure at 1.8 A resolution and biochemical characterizations of the A128V mutant implicated in chronic granulomatous disease. J. Biol. Chem. 276:21627–21631 PubMed

Tsukahara F, Urakawa I, Hattori M, Hirai M, Ohba K, Yoshioka T, Sakaki Y, Muraki T. 1998. Molecular characterization of the mouse mtprd gene, a homologue of human TPRD: unique gene expression suggesting its critical role in the pathophysiology of Down syndrome. J. Biochem. 123:1055–1063 PubMed

Cliff MJ, Harris R, Barford D, Ladbury JE, Williams MA. 2006. Conformational diversity in the TPR domain-mediated interaction of protein phosphatase 5 with Hsp90. Structure 14:415–426 PubMed

Scheufler C, Brinker A, Bourenkov G, Pegoraro S, Moroder L, Bartunik H, Hartl FU, Moarefi I. 2000. Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Cell 101:199–210 PubMed

Zhang Y, Chan DC. 2007. Structural basis for recruitment of mitochondrial fission complexes by Fis1. Proc. Natl. Acad. Sci. U. S. A. 104:18526–18530 PubMed PMC

Cortajarena AL, Regan L. 2006. Ligand binding by TPR domains. Protein Sci. 15:1193–1198 PubMed PMC

Cortajarena AL, Kajander T, Pan W, Cocco MJ, Regan L. 2004. Protein design to understand peptide ligand recognition by tetratricopeptide repeat proteins. Protein Eng. Des. Sel. 17:399–409 PubMed

Brinker A, Scheufler C, Von Der Mulbe F, Fleckenstein B, Herrmann C, Jung G, Moarefi I, Hartl FU. 2002. Ligand discrimination by TPR domains. Relevance and selectivity of EEVD-recognition in Hsp70 x Hop x Hsp90 complexes. J. Biol. Chem. 277:19265–19275 PubMed

Eckert K, Saliou JM, Monlezun L, Vigouroux A, Atmane N, Caillat C, Quevillon-Cheruel S, Madiona K, Nicaise M, Lazereg S, Van Dorsselaer A, Sanglier-Cianferani S, Meyer P, Morera S. 2010. The Pih1-Tah1 cochaperone complex inhibits Hsp90 molecular chaperone ATPase activity. J. Biol. Chem. 285:31304–31312 PubMed PMC

Krachler AM, Sharma A, Kleanthous C. 2010. Self-association of TPR domains: lessons learned from a designed, consensus-based TPR oligomer. Proteins 78:2131–2143 PubMed

Lee JR, Lee SS, Jang HH, Lee YM, Park JH, Park SC, Moon JC, Park SK, Kim SY, Lee SY, Chae HB, Jung YJ, Kim WY, Shin MR, Cheong GW, Kim MG, Kang KR, Lee KO, Yun DJ, Lee SY. 2009. Heat-shock dependent oligomeric status alters the function of a plant-specific thioredoxin-like protein, AtTDX. Proc. Natl. Acad. Sci. U. S. A. 106:5978–5983 PubMed PMC

Zeytuni N, Ozyamak E, Ben-Harush K, Davidov G, Levin M, Gat Y, Moyal T, Brik A, Komeili A, Zarivach R. 2011. Self-recognition mechanism of MamA, a magnetosome-associated TPR-containing protein, promotes complex assembly. Proc. Natl. Acad. Sci. U. S. A. 108:E480–E487 PubMed PMC

Jínek M, Rehwinkel J, Lazarus BD, Izaurralde E, Hanover JA, Conti E. 2004. The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin alpha. Nat. Struct. Mol. Biol. 11:1001–1007 PubMed

Wu Y, Sha B. 2006. Crystal structure of yeast mitochondrial outer membrane translocon member Tom70p. Nat. Struct. Mol. Biol. 13:589–593 PubMed

Main ER, Jackson SE, Regan L. 2003. The folding and design of repeat proteins: reaching a consensus. Curr. Opin. Struct. Biol. 13:482–489 PubMed

Main ER, Xiong Y, Cocco MJ, D'Andrea L, Regan L. 2003. Design of stable alpha-helical arrays from an idealized TPR motif. Structure 11:497–508 PubMed

Sonnhammer EL, Eddy SR, Durbin R. 1997. Pfam: a comprehensive database of protein domain families based on seed alignments. Proteins 28:405–420 PubMed

Schultz J, Milpetz F, Bork P, Ponting CP. 1998. SMART, a simple modular architecture research tool: identification of signaling domains. Proc. Natl. Acad. Sci. U. S. A. 95:5857–5864 PubMed PMC

Karpenahalli MR, Lupas AN, Soding J. 2007. TPRpred: a tool for prediction of TPR-, PPR- and SEL1-like repeats from protein sequences. BMC Bioinformatics 8:2 doi:10.1186/1471-2105-8-2 PubMed DOI PMC

Bröms JE, Edqvist PJ, Forsberg A, Francis MS. 2006. Tetratricopeptide repeats are essential for PcrH chaperone function in Pseudomonas aeruginosa type III secretion. FEMS Microbiol. Lett. 256:57–66 PubMed

Edqvist PJ, Bröms JE, Betts HJ, Forsberg A, Pallen MJ, Francis MS. 2006. Tetratricopeptide repeats in the type III secretion chaperone, LcrH: their role in substrate binding and secretion. Mol. Microbiol. 59:31–44 PubMed

Chakraborty S, Monfett M, Maier TM, Benach JL, Frank DW, Thanassi DG. 2008. Type IV pili in Francisella tularensis: roles of pilF and pilT in fiber assembly, host cell adherence, and virulence. Infect. Immun. 76:2852–2861 PubMed PMC

Chao J, Wong D, Zheng X, Poirier V, Bach H, Hmama Z, Av-Gay Y. 2010. Protein kinase and phosphatase signaling in Mycobacterium tuberculosis physiology and pathogenesis. Biochim. Biophys. Acta 1804:620–627 PubMed

Pallen MJ, Francis MS, Futterer K. 2003. Tetratricopeptide-like repeats in type-III-secretion chaperones and regulators. FEMS Microbiol. Lett. 223:53–60 PubMed

Mueller CA, Broz P, Cornelis GR. 2008. The type III secretion system tip complex and translocon. Mol. Microbiol. 68:1085–1095 PubMed

Salomonsson EN, Forslund A-L, Forsberg A. 2011. Type IV pili in Francisella—a virulence trait in an intracellular pathogen. Front. Microbiol. 2:29 doi:10.3389/fmicb.2011.00029 PubMed DOI PMC

Bröms JE, Forslund A-L, Forsberg A, Francis MS. 2003. PcrH of Pseudomonas aeruginosa is essential for secretion and assembly of the type III translocon. J. Infect. Dis. 188:1909–1921 PubMed

Mavris M, Page AL, Tournebize R, Demers B, Sansonetti P, Parsot C. 2002. Regulation of transcription by the activity of the Shigella flexneri type III secretion apparatus. Mol. Microbiol. 43:1543–1553 PubMed

Ménard R, Sansonetti P, Parsot C. 1994. The secretion of the Shigella flexneri Ipa invasins is activated by epithelial cells and controlled by IpaB and IpaD. EMBO J. 13:5293–5302 PubMed PMC

Watson AA, Alm RA, Mattick JS. 1996. Identification of a gene, pilF, required for type 4 fimbrial biogenesis and twitching motility in Pseudomonas aeruginosa. Gene 180:49–56 PubMed

Kondo Y, Ohara N, Sato K, Yoshimura M, Yukitake H, Naito M, Fujiwara T, Nakayama K. 2010. Tetratricopeptide repeat protein-associated proteins contribute to the virulence of Porphyromonas gingivalis. Infect. Immun. 78:2846–2856 PubMed PMC

Walburger A, Koul A, Ferrari G, Nguyen L, Prescianotto-Baschong C, Huygen K, Klebl B, Thompson C, Bacher G, Pieters J. 2004. Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 304:1800–1804 PubMed

Asare R, Abu Kwaik Y. 2010. Molecular complexity orchestrates modulation of phagosome biogenesis and escape to the cytosol of macrophages by Francisella tularensis. Environ. Microbiol. 12:2559–2586 PubMed PMC

Qin A, Mann BJ. 2006. Identification of transposon insertion mutants of Francisella tularensis tularensis strain Schu S4 deficient in intracellular replication in the hepatic cell line HepG2. BMC Microbiol. 6:69 doi:10.1186/1471-2180-6-69 PubMed DOI PMC

Dieppedale J, Sobral D, Dupuis M, Dubail I, Klimentova J, Stulik J, Postic G, Frapy E, Meibom KL, Barel M, Charbit A. 2011. Identification of a putative chaperone involved in stress resistance and virulence in Francisella tularensis. Infect. Immun. 79:1428–1439 PubMed PMC

Cornelis GR, Wolf-Watz H. 1997. The Yersinia Yop virulon: a bacterial system for subverting eukaryotic cells. Mol. Microbiol. 23:861–867 PubMed

Navarro L, Alto NM, Dixon JE. 2005. Functions of the Yersinia effector proteins in inhibiting host immune responses. Curr. Opin. Microbiol. 8:21–27 PubMed

Francis MS, Lloyd SA, Wolf-Watz H. 2001. The type III secretion chaperone LcrH co-operates with YopD to establish a negative, regulatory loop for control of Yop synthesis in Yersinia pseudotuberculosis. Mol. Microbiol. 42:1075–1093 PubMed

Bröms JE, Edqvist PJ, Carlsson KE, Forsberg A, Francis MS. 2005. Mapping of a YscY binding domain within the LcrH chaperone that is required for regulation of Yersinia type III secretion. J. Bacteriol. 187:7738–7752 PubMed PMC

Finck-Barbançon V, Goranson J, Zhu L, Sawa T, Wiener-Kronish JP, Fleiszig SM, Wu C, Mende-Mueller L, Frank DW. 1997. ExoU expression by Pseudomonas aeruginosa correlates with acute cytotoxicity and epithelial injury. Mol. Microbiol. 25:547–557 PubMed

Frithz-Lindsten E, Du Y, Rosqvist R, Forsberg A. 1997. Intracellular targeting of exoenzyme S of Pseudomonas aeruginosa via type III-dependent translocation induces phagocytosis resistance, cytotoxicity and disruption of actin microfilaments. Mol. Microbiol. 25:1125–1139 PubMed

Yahr TL, Goranson J, Frank DW. 1996. Exoenzyme S of Pseudomonas aeruginosa is secreted by a type III pathway. Mol. Microbiol. 22:991–1003 PubMed

Yahr TL, Vallis AJ, Hancock MK, Barbieri JT, Frank DW. 1998. ExoY, an adenylate cyclase secreted by the Pseudomonas aeruginosa type III system. Proc. Natl. Acad. Sci. U. S. A. 95:13899–13904 PubMed PMC

Kaufman MR, Jia J, Zeng L, Ha U, Chow M, Jin S. 2000. Pseudomonas aeruginosa mediated apoptosis requires the ADP-ribosylating activity of ExoS. Microbiology 146(Pt 10):2531–2541 PubMed

Sundin C, Wolfgang MC, Lory S, Forsberg A, Frithz-Lindsten E. 2002. Type IV pili are not specifically required for contact dependent translocation of exoenzymes by Pseudomonas aeruginosa. Microb. Pathog. 33:265–277 PubMed

Allmond LR, Karaca TJ, Nguyen VN, Nguyen T, Wiener-Kronish JP, Sawa T. 2003. Protein binding between PcrG-PcrV and PcrH-PopB/PopD encoded by the pcrGVH-popBD operon of the Pseudomonas aeruginosa type III secretion system. Infect. Immun. 71:2230–2233 PubMed PMC

Schroeder GN, Hilbi H. 2008. Molecular pathogenesis of Shigella spp.: controlling host cell signaling, invasion, and death by type III secretion. Clin. Microbiol. Rev. 21:134–156 PubMed PMC

Maurelli AT, Baudry B, d'Hauteville H, Hale TL, Sansonetti PJ. 1985. Cloning of plasmid DNA sequences involved in invasion of HeLa cells by Shigella flexneri. Infect. Immun. 49:164–171 PubMed PMC

Ménard R, Prevost MC, Gounon P, Sansonetti P, Dehio C. 1996. The secreted Ipa complex of Shigella flexneri promotes entry into mammalian cells. Proc. Natl. Acad. Sci. U. S. A. 93:1254–1258 PubMed PMC

Ménard R, Sansonetti PJ, Parsot C. 1993. Nonpolar mutagenesis of the ipa genes defines IpaB, IpaC, and IpaD as effectors of Shigella flexneri entry into epithelial cells. J. Bacteriol. 175:5899–5906 PubMed PMC

Parsot C, Ageron E, Penno C, Mavris M, Jamoussi K, d'Hauteville H, Sansonetti P, Demers B. 2005. A secreted anti-activator, OspD1, and its chaperone, Spa15, are involved in the control of transcription by the type III secretion apparatus activity in Shigella flexneri. Mol. Microbiol. 56:1627–1635 PubMed

Zychlinsky A, Kenny B, Ménard R, Prevost MC, Holland IB, Sansonetti PJ. 1994. IpaB mediates macrophage apoptosis induced by Shigella flexneri. Mol. Microbiol. 11:619–627 PubMed

Birket SE, Harrington AT, Espina M, Smith ND, Terry CM, Darboe N, Markham AP, Middaugh CR, Picking WL, Picking WD. 2007. Preparation and characterization of translocator/chaperone complexes and their component proteins from Shigella flexneri. Biochemistry 46:8128–8137 PubMed

Kane CD, Schuch R, Day WA, Jr, Maurelli AT. 2002. MxiE regulates intracellular expression of factors secreted by the Shigella flexneri 2a type III secretion system. J. Bacteriol. 184:4409–4419 PubMed PMC

Barta ML, Zhang L, Picking WL, Geisbrecht BV. 2010. Evidence for alternative quaternary structure in a bacterial type III secretion system chaperone. BMC Struct. Biol. 10:21 doi:10.1186/1472-6807-10-21 PubMed DOI PMC

Koo J, Tammam S, Ku SY, Sampaleanu LM, Burrows LL, Howell PL. 2008. PilF is an outer membrane lipoprotein required for multimerization and localization of the Pseudomonas aeruginosa type IV pilus secretin. J. Bacteriol. 190:6961–6969 PubMed PMC

Scherr N, Honnappa S, Kunz G, Mueller P, Jayachandran R, Winkler F, Pieters J, Steinmetz MO. 2007. Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. U. S. A. 104:12151–12156 PubMed PMC

Tiwari D, Singh RK, Goswami K, Verma SK, Prakash B, Nandicoori VK. 2009. Key residues in Mycobacterium tuberculosis protein kinase G play a role in regulating kinase activity and survival in the host. J. Biol. Chem. 284:27467–27479 PubMed PMC

Cowley S, Ko M, Pick N, Chow R, Downing KJ, Gordhan BG, Betts JC, Mizrahi V, Smith DA, Stokes RW, Av-Gay Y. 2004. The Mycobacterium tuberculosis protein serine/threonine kinase PknG is linked to cellular glutamate/glutamine levels and is important for growth in vivo. Mol. Microbiol. 52:1691–1702 PubMed

Cortajarena AL, Yi F, Regan L. 2008. Designed TPR modules as novel anticancer agents. ACS Chem. Biol. 3:161–166 PubMed

Horibe T, Kohno M, Haramoto M, Ohara K, Kawakami K. 2011. Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent. J. Transl. Med. 9:8 doi:10.1186/1479-5876-9-8 PubMed DOI PMC

Oyston PC, Quarry JE. 2005. Tularemia vaccine: past, present and future. Antonie Van Leeuwenhoek 87:277–281 PubMed

Protein-Protein Interactions Modulate the Docking-Dependent E3-Ubiquitin Ligase Activity of Carboxy-Terminus of Hsc70-Interacting Protein (CHIP)

Characterization of tetratricopeptide repeat-like proteins in Francisella tularensis and identification of a novel locus required for virulence