SecReT4
T4SS ID38
StrainHelicobacter pylori J99
Repliconchromosome [Browse all T4SS(s) in this replicon]
AccessionNC_000921
Location511642..542832
NameCag
Functioneffector translocation
ClassificationType IVA; Type P
experimental Experimental investigation has been performed on this T4SS.

T4SS components
ComponentCagCCagDCagECagFCagGCagHCagICagLCagN
Number111111111
ComponentCagMCagTCagUCagVCagWCagXCagYCagZCagalpha
Number111111111
ComponentCagbetaCaggammaCagdelta
Number111

The information of T4SS components from NC_000921
#Locus tag (Gene)Coordinates [+/-], size (bp)Protein GIProductComponent
1jhp0466 (era)507322..508227 [+], 90615611533GTP-binding protein Era 
2jhp0467508224..509216 [+], 99315611534hypothetical protein 
3jhp0468509304..510155 [-], 85215611535hypothetical protein 
4jhp0469 (orf6)510500..510847 [+], 34815611536cag island protein 
5jhp0470 (orf7)510990..511649 [+], 66015611537cag island protein 
6jhp0471 (orf8)511642..513087 [+], 144615611538cag island protein  Cagdelta
7jhp0472 (orf9)513097..513606 [+], 51015611539cag island protein  Caggamma
8jhp0473 (virD4)514088..516334 [-], 224715611540cag island protein, DNA transfer protein  Cagbeta
9jhp0474 (virB11_1)516343..517335 [-], 99315611541cag island protein, DNA transfer protein  Cagalpha
10jhp0475 (orf12)517340..517939 [-], 60015611542cag island protein  CagZ
11jhp0476 (orf13/14)518074..523533 [-], 546015611543cag island protein  CagY
12jhp0477 (orf15)523548..525116 [-], 156915611544cag island protein  CagX
13jhp0478 (orf16)525169..526776 [-], 160815611545cag island protein  CagW
14jhp0479 (orf17)526781..527539 [-], 75915611546cag island protein  CagV
15jhp0480 (orf18)527921..528577 [+], 65715611547cag island protein  CagU
16jhp0481 (cagT)528613..529455 [+], 84315611548cag island protein  CagT
17jhp0482 (cagS)529660..530259 [-], 60015611549cag island protein 
18jhp0483 (cagQ)530698..531078 [-], 38115611550cag island protein 
19jhp0484 (cagP)531505..531849 [-], 34515611551cag island protein 
20jhp0485 (cagM)532464..533594 [+], 113115611552cag island protein  CagM
21jhp0486 (cagN)533609..534529 [+], 92115611553cag island protein  CagN
22jhp0487 (cagL)534611..535324 [-], 71415611554cag island protein  CagLinteraction
23jhp0488 (cagI)535321..536466 [-], 114615611555cag island protein  CagI
24jhp0489 (cagH)536477..537589 [-], 111315611556cag island protein  CagH
25jhp0490 (cagG)537606..538034 [-], 42915611557cag island protein  CagG
26jhp0491 (cagF)538089..538895 [-], 80715611558cag island protein  CagFaccesspry protein
27jhp0492 (cagE)538897..541848 [-], 295215611559DNA transfer protein  CagE
28jhp0493 (cagD)541857..542483 [-], 62715611560cag island protein  CagD
29jhp0494 (cagC)542485..542832 [-], 34815611561cag island protein  CagC
30jhp0495 (cagA)543605..547108 [+], 350415611562cag island protein, cytotoxicity associated immunodominant antigen  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  *
1jhp0495 (cagA)543605..547108 [+], 350415611562cag island protein, cytotoxicity associated immunodominant antigenexperimental  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) (15611558)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/SubstrateSourceFunctionReference
1CagA (15611562)SHP-2humanCagA 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 (15611562)growth factor receptor bound 2 (Grb2)unknownCagA can interact with Grb2, which result in activing the MEK/ERK pathway and leads to cell scattering and proliferation.(2) PubMed: 12419219insolico
3CagA (15611562)PAR1/MARK kinasehumanPAR1 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 (15611562)Apoptosis-stimulating of p53 protein 2 (ASPP2)humanASPP2 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 (15611562)protein kinase C-related kinase 2 (PRK2)humanPRK2 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 (15611562)Glycogen synthase kinase 3 (GSK-3)humanCagA 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 (15611562)c-MethumanCagA 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 (15611562)E-cadherinhumanCagA 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 (15611562)host membrane phosphatidylserineunknownCagA 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 (15611562)c-Abl tyrosine kinasehumanCagA directly targets to c-Abl and localizes in in focal adhesion complexes and membrane ruffles.(10) PubMed: 17160020insolico
11CagA (15611562)αPixhumanCagA 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 (15611562)scaffolding protein ZO-1human, canineCagA 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: 12775840insolico
13CagA (15611562)integrin α5β1 receptorhumanCagA binds interface with α5β1 integrin.It is an essential step for the translocation process of CagA into the host cell.(13) PubMed: 22908298insolico
14CagA (15611562)TNF receptor-associated factor 1 and 4-1BB (TRAF1 and 4-1BB)humanCagA promotes the proliferation and inhibits the apoptosis of GES-1 cells via upregulated TRAF1/4-1BB.(14) PubMed: 28627614insolico
15CagA (15611562)Adapter molecule crkhumanCagA binding Crk adaptor proteins is important for Helicobacter pylori-induced loss of gastric epithelial cell adhesion.(15) PubMed: 16275761experimental
16CagA (15611562)SHP-1humanSHP1 interacts with CagA to potentiate the phosphatase activity of SHP1 so that it dampens the oncogenic action of CagA.(16) PubMed: 27572445insolico
17CagA (15611562)Transforming growth factor-beta-activated kinase 1 (TAK1)humanCagA interacts with TAK1 and enhances its activity to activate NF-kappaB through the ubiquitination of TAK1.(17) PubMed: 19820695insolico
18CagA (15611562)Myeloid cell leukemia sequence-1 (MCL1)mongolian gerbilCagA 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 (15611554)integrin α5β1 receptorhumanCagL 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 (15611554)integrin αvβ3humanHost cell docking of T4SS.(20) PubMed: 21915696insolico
21CagL (15611554)integrin αvβ5humanCagL/integrin β5 signalling complex is important for H pylori induced gastrin expression.(21) PubMed: 22287591insolico
22CagL (15611554)integrin αvβ6humanαvβ6 is a specific, high affinity receptor for CagL.(22) PubMed: 31197920insolico
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) Aras RA; Fischer W; Perez-Perez GI; Crosatti M; Ando T; Haas R; Blaser MJ (2003). Plasticity of repetitive DNA sequences within a bacterial (Type IV) secretion system component. J Exp Med. 198(9):1349-60. [PudMed:14581606] experimental
(6) Backert S; Churin Y; Meyer TF (2002). Helicobacter pylori type IV secretion, host cell signalling and vaccine development. Keio J Med. 51 Suppl 2:6-14. [PudMed:12528929] experimental
 
experimental This literature contains experimental investigation
in_silico This literature contains bioinformatics investigation