SecReT4
T4SS ID39
StrainHelicobacter pylori G27
Repliconchromosome [Browse all T4SS(s) in this replicon]
AccessionNC_011333
Location514715..547464
NameCag
Functioneffector translocation
ClassificationType IVA; Type P
experimental Experimental investigation has been performed on this T4SS.

T4SS components
ComponentCagCCagDCagECagFCagGCagHCagICagLCagN
Number111111111
ComponentCagMCagTCagUCagVCagWCagXCagYCagZCagalpha
Number111111011
ComponentCagbetaCaggammaCagdelta
Number111

The information of T4SS components from NC_011333
#Locus tag (Gene)Coordinates [+/-], size (bp)Protein GIProductComponent
1HPG27_476 (era)510908..511813 [+], 906208434439GTP-binding protein Era 
2HPG27_477511810..512802 [+], 993208434440hypothetical protein 
3HPG27_478512885..513766 [-], 882208434441hypothetical protein 
4HPG27_479 (cag1)513910..514257 [+], 348208434442cag pathogenicity island protein 1 
5HPG27_480514464..514715 [+], 252208434443hypothetical protein 
6HPG27_481 (cag3)514715..516160 [+], 1446208434444cag pathogenicity island protein 3  Cagdelta
7HPG27_482 (cag4)516165..516674 [+], 510208434445cag pathogenicity island protein 4  Caggamma
8HPG27_483 (cag5)516793..519039 [-], 2247208434446cag pathogenicity island protein 5  Cagbeta
9HPG27_484519048..520040 [-], 993208434447virB11-like cag pathogenicity islandencoded protein / ATPase  Cagalpha
10HPG27_485 (cagZ)520045..520644 [-], 600208434448cag pathogenicity island protein Z  CagZ
11HPG27_487 (cagX)526506..528071 [-], 1566208434449cag pathogenicity island protein X  CagX
12HPG27_488 (cagW)528123..529730 [-], 1608208434450cag pathogenicity island protein W  CagW
13HPG27_489 (cagV)529735..530493 [-], 759208434451cag pathogenicity island protein V  CagV
14HPG27_490 (cagU)530890..531540 [+], 651208434452cag pathogenicity island protein U  CagU
15HPG27_491 (cagT)531553..532395 [+], 843208434453cag pathogenicity island protein T  CagT
16HPG27_492 (cagS)532592..533191 [-], 600208434454cag pathogenicity island protein S 
17HPG27_493 (cagQ)535518..535823 [-], 306208434455cag pathogenicity island protein Q 
18HPG27_494535835..536014 [-], 180208434456hypothetical protein 
19HPG27_495 (cagM)537100..538230 [+], 1131208434457cag pathogenicity island protein M  CagM
20HPG27_496 (cagN)538245..539165 [+], 921208434458cag pathogenicity island protein N  CagN
21HPG27_497 (cagL)539247..539960 [-], 714208434459cag pathogenicity island protein L  CagLinteraction
22HPG27_498 (cagI)539957..541033 [-], 1077208434460cag pathogenicity island protein I  CagI
23HPG27_499 (cagH)541113..542045 [-], 933208434462cag pathogenicity island protein H  CagH
24HPG27_500542044..542244 [+], 201208434461hypothetical protein 
25HPG27_501 (cagG)542241..542669 [-], 429208434463cag pathogenicity island protein G  CagG
26HPG27_502 (cagF)542724..543530 [-], 807208434464cag pathogenicity island protein F  CagFaccesspry protein
27HPG27_503 (cagE)543532..546483 [-], 2952208434465cag pathogenicity island protein E  CagE
28HPG27_504 (cagD)546492..547115 [-], 624208434466cag pathogenicity island protein D  CagD
29HPG27_505 (cagC)547117..547464 [-], 348208434467cag pathogenicity island protein C  CagC
30HPG27_506 (cagB)547609..547836 [-], 228208434468cag pathogenicity island protein B 
31HPG27_507 (cagA)548263..551955 [+], 3693208434469cytotoxin-associated protein A  interaction
 
accesspry protein This T4SS contains information of accessory protein.
interaction This T4SS contains information of interaction.
flank Genes in the 5-Kb flanking regions if available, or non-essential genes in the T4SS gene cluster if any.

Download FASTA format files
Proteins        Genes

Effectors
CagA; Peptidoglycan

The information of protein effectors
#Locus tag (Gene)Coordinates [+/-], size (bp)Protein GIProduct  *
1HPG27_507 (cagA)548263..551955 [+], 3693208434469cytotoxin-associated protein Aexperimental  CagAinteraction
experimental T4SE derived from experimental literature.
interaction This effector contains information of interaction.

Download FASTA format files
Proteins        Genes
The information on requirements for T4SS substrate-channel docking

Certain T4SS substrates require secretion chaperones for translocation. These chaperones often possess physical properties (small size of 15 kDa, acidic pI, and amphipathic helices) resembling those of chaperones associated with the type III secretion systems, a family of macromolecular translocation systems ancestrally related to bacterial flagella.

#Accessory protein(GI)motif(s)Substrate(s)FunctionReference
1CagF (chaperone) (208434464)CT20aa and an intact N terminusCagAThe CagA-binding protein CagF is a secretion chaperone-like protein that interacts with a 100 aa region that is adjacent to the C-terminal secretion signal of CagA.CagF is a translocation factor for CagA, but is not translocated by the type IV apparatus.(1) PubMed: 17768234
Tips:
1.Substrate(s): For the conjugation systems, the listed proteins are relaxases that bind a cognate T4CP and are delivered to recipient cells. For the effector translocator systems, the listed proteins are effectors that play a role in the infection processes of the bacterial pathogen.
2.motif(s):The motifs listed are required for substrate translocation. In some cases, the protein or its C-terminal fragment (CT) is sufficient to mediate translocation to target cells, as shown by fusion to a reporter protein such as Cre recombinase or adenylate cyclase. Amino acids (aa) at positions listed relative to the C-terminal fragment (subscript) are required for translocation, as shown by mutational analysis. ND, not determined. Parentheses indicate that the interaction between a protein substrate and a cognate T4CP has been experimentally shown.
3.Accessory protein: Accessory factors required for T4SS channel docking or translocation. The proposed function in mediating substrate-T4SS channel docking is shown in parentheses.PubMed:19946141

(1) Pattis I; Weiss E; Laugks R; Haas R; Fischer W (2007). The Helicobacter pylori CagF protein is a type IV secretion chaperone-like molecule that binds close to the C-terminal secretion signal of the CagA effector protein. Microbiology. 153(Pt 9):2896-909. [PudMed:17768234] experimental
The information on host-pathogen interaction.

#Name(Protein GI)Host site/SubstrateFunctionReference
1CagA (208434469)SHP-2CagA is translocated from the bacteria into gastric epithelial cells. It physically interacts with SHP-2 to modify cellular functions and perturb mammalian signal transduction machineries. This may induce abnormal proliferation and movement of gastric epithelial cells and promote the acquisition of a cellular transformed phenotype.(1) PubMed: 11743164insolico
2CagA (208434469)growth factor receptor bound 2 (Grb2)CagA can interact with Grb2, which result in activing the MEK/ERK pathway and leads to cell scattering and proliferation.(2) PubMed: 12419219insolico
3CagA (208434469)PAR1/MARK kinasePAR1 is a key target of H. pylori CagA in the disorganization of gastric epithelial architecture underlying mucosal damage, inflammation and carcinogenesis. H. pylori CagA specifically interacts with PAR1/MARK kinase, which inhibits PAR1 kinase activity and prevents atypical protein kinase C (aPKC)-mediated PAR1 phosphorylation.(3) PubMed: 17507984insolico
4CagA (208434469)Apoptosis-stimulating of p53 protein 2 (ASPP2)ASPP2 is a tumor suppressor that activates the p53-mediated apoptotic response upon cellular stress. Direct interaction between CagA and ASPP2 changes the function of ASPP2 and leads to the decreased survival of H. pylori infected cells.(4) PubMed: 24474782insolico
5CagA (208434469)protein kinase C-related kinase 2 (PRK2)PRK2 has been involved in establishment of cell polarity and cytoskeletal rearrangements. CagA inhibits kinase activity of PRK2 to further manipulate cancer-related signalling pathways.(5) PubMed: 26041307insolico
6CagA (208434469)Glycogen synthase kinase 3 (GSK-3)CagA binds GSK-3 to reduce its activity by cause it to shift to an insoluble fraction. Then cagA induce a Snail-mediated epithelial mesenchymal transition via the depletion of GSK-3.(6) PubMed: 25055241insolico
7CagA (208434469)c-MetCagA interacts with the c-Met receptor to modulates cellular functions via deregulating c-Met receptor signaling and is involved in invasive growth of tumor cells.(7) PubMed: 12719469insolico
8CagA (208434469)E-cadherinCagA interacts with E-cadherin to impair the complex formation between E-cadherin and beta-catenin and promotes intestinal transdifferentiation in gastric epithelial cells.(8) PubMed: 17237808insolico
9CagA (208434469)host membrane phosphatidylserineCagA interacts whith phosphatidylserine to be tethered to the inner leaflet of the plasma membrane. Then it binds the PAR1/MARK to induce polarity and junctional defects.(9) PubMed: 20478541experimental
10CagA (208434469)c-Abl tyrosine kinaseCagA directly targets to c-Abl and localizes in in focal adhesion complexes and membrane ruffles.(10) PubMed: 17160020insolico
11CagA (208434469)αPixCagA was delivered into AGS cells and interacted with αPix to activates PAK1, ERK and NF-kappaB. Then it induces IL-8 expression in infected gastric epithelial cells.(11) PubMed: 19672789insolico
12CagA (208434469)scaffolding protein ZO-1CagA associates with epithelial tight-junction ZO-1 and the transmembrane protein junctional adhesion molecule to alter the function and composition of the apical-junctional complex.(12) PubMed: 12775840experimental
13CagA (208434469)integrin α5β1 receptorCagA binds interface with α5β1 integrin.It is an essential step for the translocation process of CagA into the host cell.(13) PubMed: 22908298insolico
14CagA (208434469)TNF receptor-associated factor 1 and 4-1BB (TRAF1 and 4-1BB)CagA promotes the proliferation and inhibits the apoptosis of GES-1 cells via upregulated TRAF1/4-1BB.(14) PubMed: 28627614insolico
15CagA (208434469)Adapter molecule crkCagA binding Crk adaptor proteins is important for Helicobacter pylori-induced loss of gastric epithelial cell adhesion.(15) PubMed: 16275761insolico
16CagA (208434469)SHP-1SHP1 interacts with CagA to potentiate the phosphatase activity of SHP1 so that it dampens the oncogenic action of CagA.(16) PubMed: 27572445insolico
17CagA (208434469)Transforming growth factor-beta-activated kinase 1 (TAK1)CagA interacts with TAK1 and enhances its activity to activate NF-kappaB through the ubiquitination of TAK1.(17) PubMed: 19820695experimental
18CagA (208434469)Myeloid cell leukemia sequence-1 (MCL1)CagA Increases MCL1 via SRE/SRF and CagA/MCL1 interplay in modulating rapid turnover of pit epithelial cells via MEK/ERK/SRE activation.(18) PubMed: 18005743insolico
19CagL (208434459)integrin α5β1 receptorCagL protein is a specialized adhesin that is targeted to the pilus surface. It binds to and activates integrin α5β1 receptor on gastric epithelial cells. This interaction triggers CagA delivery into target cells.(19) PubMed: 17943123insolico
20CagL (208434459)integrin αvβ3Host cell docking of T4SS.(20) PubMed: 21915696insolico
21CagL (208434459)integrin αvβ5CagL/integrin β5 signalling complex is important for H pylori induced gastrin expression.(21) PubMed: 22287591insolico
22CagL (208434459)integrin αvβ6αvβ6 is a specific, high affinity receptor for CagL.(22) PubMed: 31197920experimental
experimental This T4SE is mentioned in the literature.
insolico This T4SE is highly identical with the protein mentioned in the literature.
(1) Higashi H et al. (2002). SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science. 295(5555):683-6. [PudMed:11743164] experimental
(2) Mimuro H et al. (2002). Grb2 is a key mediator of helicobacter pylori CagA protein activities. Mol Cell. 10(4):745-55. [PudMed:12419219] experimental
(3) Saadat I et al. (2007). Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature. 447(7142):330-3. [PudMed:17507984] experimental
(4) Nešić D et al. (2014). Structure of the Helicobacter pylori CagA oncoprotein bound to the human tumor suppressor ASPP2. Proc Natl Acad Sci U S A. 111(4):1562-7. [PudMed:24474782] experimental
(5) Mishra JP et al. (2015). CagA of Helicobacter pylori interacts with and inhibits the serine-threonine kinase PRK2. Cell Microbiol. 17(11):1670-82. [PudMed:26041307] experimental
(6) Lee DG et al. (2014). Helicobacter pylori CagA promotes Snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity. Nat Commun. 5:4423. [PudMed:25055241] experimental
(7) Churin Y et al. (2003). Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J Cell Biol. 161(2):249-55. [PudMed:12719469] experimental
(8) Murata-Kamiya N et al. (2007). Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene. 26(32):4617-26. [PudMed:17237808] experimental
(9) Murata-Kamiya N; Kikuchi K; Hayashi T; Higashi H; Hatakeyama M (2010). Helicobacter pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of the CagA oncoprotein. Cell Host Microbe. 7(5):399-411. [PudMed:20478541] experimental
(10) Poppe M; Feller SM; Romer G; Wessler S (2007). Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility. Oncogene. 26(24):3462-72. [PudMed:17160020] experimental
(11) Lim JW et al. (2009). alphaPix interacts with Helicobacter pylori CagA to induce IL-8 expression in gastric epithelial cells. Scand J Gastroenterol. 44(10):1166-72. [PudMed:19672789] experimental
(12) Amieva MR et al. (2003). Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 300(5624):1430-4. [PudMed:12775840] experimental
(13) Kaplan-Türköz B et al. (2012). Structural insights into Helicobacter pylori oncoprotein CagA interaction with β1 integrin. Proc Natl Acad Sci U S A. 109(36):14640-5. [PudMed:22908298] experimental
(14) Wang F et al. (2017). CagA promotes proliferation and inhibits apoptosis of GES-1 cells by upregulating TRAF1/4-1BB. Mol Med Rep. 16(2):1262-1268. [PudMed:28627614] experimental
(15) Suzuki M et al. (2005). Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. J Exp Med. 202(9):1235-47. [PudMed:16275761] experimental
(16) Saju P et al. (2016). Host SHP1 phosphatase antagonizes Helicobacter pylori CagA and can be downregulated by Epstein-Barr virus. Nat Microbiol. 1:16026. [PudMed:27572445] experimental
(17) Lamb A et al. (2009). Helicobacter pylori CagA activates NF-kappaB by targeting TAK1 for TRAF6-mediated Lys 63 ubiquitination. EMBO Rep. 10(11):1242-9. [PudMed:19820695] experimental
(18) Mimuro H et al. (2007). Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach. Cell Host Microbe. 2(4):250-63. [PudMed:18005743] experimental
(19) Kwok T; Zabler D; Urman S; Rohde M; Hartig R; Wessler S; Misselwitz R; Berger J; Sewald N; Konig W; Backert S (2007). Helicobacter exploits integrin for type IV secretion and kinase activation. Nature. 449(7164):862-6. [PudMed:17943123] experimental
(20) Conradi J; Huber S; Gaus K; Mertink F; Royo Gracia S; Strijowski U; Backert S; Sewald N (2012). Cyclic RGD peptides interfere with binding of the Helicobacter pylori protein CagL to integrins alpha(V)beta (3) and alpha (5)beta (1). Amino Acids. 43(1):219-32. [PudMed:21915696] experimental
(21) Wiedemann T et al. (2012). Helicobacter pylori CagL dependent induction of gastrin expression via a novel αvβ5-integrin-integrin linked kinase signalling complex. Gut. 61(7):986-96. [PudMed:22287591] experimental
(22) Buß M et al. (2019). Specific high affinity interaction of Helicobacter pylori CagL with integrin αV β6 promotes type IV secretion of CagA into human cells. FEBS J. . [PudMed:31197920] experimental
(1) You Y; He L; Zhang M; Fu J; Gu Y; Zhang B; Tao X; Zhang J (2012). Comparative Genomics of Helicobacter pylori Strains of China Associated with Different Clinical Outcome. PLoS One. 7(6):e38528. [PudMed:22701658] experimental in_silico
(2) Rizzato C; Torres J; Plummer M; Munoz N; Franceschi S; Camorlinga-Ponce M; Fuentes-Panana EM; Canzian F; Kato I (2012). Variations in Helicobacter pylori cytotoxin-associated genes and their influence in progression to gastric cancer: implications for prevention. PLoS One. 7(1):e29605. [PudMed:22235308] experimental in_silico
(3) Tegtmeyer N; Backert S (2011). Role of Abl and Src family kinases in actin-cytoskeletal rearrangements induced by the Helicobacter pylori CagA protein. Eur J Cell Biol. 90(11):880-90. [PudMed:21247656]
(4) Fischer W; Windhager L; Rohrer S; Zeiller M; Karnholz A; Hoffmann R; Zimmer R; Haas R (2010). Strain-specific genes of Helicobacter pylori: genome evolution driven by a novel type IV secretion system and genomic island transfer. Nucleic Acids Res. 38(18):6089-101. [PudMed:20478826] experimental in_silico
(5) Fehri LF; Rechner C; Janssen S; Mak TN; Holland C; Bartfeld S; Bruggemann H; Meyer TF (2009). Helicobacter pylori-induced modification of the histone H3 phosphorylation status in gastric epithelial cells reflects its impact on cell cycle regulation. Epigenetics. 4(8):577-86. [PudMed:20081355] experimental
(6) Allison CC; Kufer TA; Kremmer E; Kaparakis M; Ferrero RL (2009). Helicobacter pylori induces MAPK phosphorylation and AP-1 activation via a NOD1-dependent mechanism. J Immunol. 183(12):8099-109. [PudMed:20007577] experimental
(7) Pinto-Santini DM; Salama NR (2009). Cag3 is a novel essential component of the Helicobacter pylori Cag type IV secretion system outer membrane subcomplex. J Bacteriol. 191(23):7343-52. [PudMed:19801411] experimental
(8) Cendron L; Couturier M; Angelini A; Barison N; Stein M; Zanotti G (2009). The Helicobacter pylori CagD (HP0545, Cag24) protein is essential for CagA translocation and maximal induction of interleukin-8 secretion. J Mol Biol. 386(1):204-17. [PudMed:19109970] experimental
(9) Couturier MR; Stein M (2008). Helicobacter pylori produces unique filaments upon host contact in vitro. Can J Microbiol. 54(7):537-48. [PudMed:18641700] experimental
(10) Hilleringmann M; Pansegrau W; Doyle M; Kaufman S; MacKichan ML; Gianfaldoni C; Ruggiero P; Covacci A (2006). Inhibitors of Helicobacter pylori ATPase Cagalpha block CagA transport and cag virulence. Microbiology. 152(Pt 10):2919-30. [PudMed:17005973] experimental
(11) Bourzac KM; Satkamp LA; Guillemin K (2006). The Helicobacter pylori cag pathogenicity island protein CagN is a bacterial membrane-associated protein that is processed at its C terminus. Infect Immun. 74(5):2537-43. [PudMed:16622188] experimental
(12) Couturier MR; Tasca E; Montecucco C; Stein M (2006). Interaction with CagF is required for translocation of CagA into the host via the Helicobacter pylori type IV secretion system. Infect Immun. 74(1):273-81. [PudMed:16368981] experimental
(13) Backert S; Kwok T; Konig W (2005). Conjugative plasmid DNA transfer in Helicobacter pylori mediated by chromosomally encoded relaxase and TraG-like proteins. Microbiology. 151(Pt 11):3493-503. [PudMed:16272373] experimental
(14) Guillemin K; Salama NR; Tompkins LS; Falkow S (2002). Cag pathogenicity island-specific responses of gastric epithelial cells to Helicobacter pylori infection. Proc Natl Acad Sci U S A. 99(23):15136-41. [PudMed:12411577] experimental
(15) Ramarao N; Gray-Owen SD; Backert S; Meyer TF (2000). Helicobacter pylori inhibits phagocytosis by professional phagocytes involving type IV secretion components. Mol Microbiol. 37(6):1389-404. [PudMed:10998171] experimental
(16) Stein M; Rappuoli R; Covacci A (2000). Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci U S A. 97(3):1263-8. [PudMed:10655519] experimental
 
experimental This literature contains experimental investigation
in_silico This literature contains bioinformatics investigation