SecReT4
T4SS ID37
StrainHelicobacter pylori HPAG1
Repliconchromosome [Browse all T4SS(s) in this replicon]
AccessionNC_008086
Location514158..545246; 1431707..1432237
NameCag
Functioneffector translocation
ClassificationType IVA; Type P
insolico Bioinformatics investigation has been performed on this T4SS.

T4SS components
ComponentCagCCagDCagECagFCagGCagHCagICagLCagN
Number112111111
ComponentCagMCagTCagUCagVCagWCagXCagYCagZCagalpha
Number111111311
ComponentCagbetaCaggammaCagdelta
Number111

The information of T4SS components from NC_008086
Region 1: 514158..545246
#Locus tag (Gene)Coordinates [+/-], size (bp)Protein GIProductComponent
1HPAG1_0491 (era)509873..510778 [+], 906108562916GTP-binding protein Era 
2HPAG1_0492510775..511767 [+], 993108562917hypothetical protein 
3HPAG1_0493511846..512700 [-], 855108562918hypothetical protein 
4HPAG1_0494512719..512958 [+], 240108562919IS606 transposase 
5HPAG1_0495513044..513391 [+], 348108562920cag pathogenicity island protein 1 
6HPAG1_0496513407..514165 [+], 759108562921HP0521B-like protein 
7HPAG1_0497514158..515603 [+], 1446108562922cag pathogenicity island protein 3  Cagdelta
8HPAG1_0498515613..516122 [+], 510108562923cag pathogenicity island protein 4  Caggamma
9HPAG1_0499516241..518487 [-], 2247108562924cag pathogenicity island protein 5  Cagbeta
10HPAG1_0500518496..519488 [-], 993108562925cag pathogenicity island encoded protein/ATPase protein  Cagalpha
11HPAG1_0501519493..520092 [-], 600108562926cag pathogenicity island protein Z  CagZ
12HPAG1_0502520227..524114 [-], 3888108562927cag pathogenicity island protein Y  CagY
13HPAG1_0503524173..526161 [-], 1989108562928cag pathogenicity island protein Y  CagY
14HPAG1_0504526176..527747 [-], 1572108562929cag pathogenicity island protein X  CagX
15HPAG1_0505527797..529404 [-], 1608108562930cag pathogenicity island protein W  CagW
16HPAG1_0506529409..530167 [-], 759108562931cag pathogenicity island protein V  CagV
17HPAG1_0507530565..531215 [+], 651108562932cag pathogenicity island protein U  CagU
18HPAG1_0508531228..532070 [+], 843108562933cag pathogenicity island protein T  CagT
19HPAG1_0510532270..532869 [-], 600108562935cag pathogenicity island protein S 
20HPAG1_0511533301..533681 [-], 381108562936cag pathogenicity island protein Q 
21HPAG1_0512534882..536012 [+], 1131108562937cag pathogenicity island protein M  CagM
22HPAG1_0513536027..536947 [+], 921108562938cag pathogenicity island protein N  CagN
23HPAG1_0514537029..537742 [-], 714108562939cag pathogenicity island protein L  CagLinteraction
24HPAG1_0515537739..538884 [-], 1146108562940cag pathogenicity island protein I  CagI
25HPAG1_0516538895..540007 [-], 1113108562941cag pathogenicity island protein H  CagH
26HPAG1_0517540024..540452 [-], 429108562942cag pathogenicity island protein G  CagG
27HPAG1_0518540507..541313 [-], 807108562943cag pathogenicity island protein F  CagFaccesspry protein
28HPAG1_0519541315..542631 [-], 1317108562944cag pathogenicity island protein E  CagE
29HPAG1_0520542661..544265 [-], 1605108562945cag pathogenicity island protein E  CagE
30HPAG1_0521544274..544924 [-], 651108562946cag pathogenicity island protein D  CagD
31HPAG1_0522544899..545246 [-], 348108562947cag pathogenicity island protein C  CagC
32HPAG1_0523545391..545618 [-], 228108562948cag pathogenicity island protein B 
33HPAG1_0524546049..549651 [+], 3603108562949cytotoxin-associated protein A  interaction
34HPAG1_0525549714..549863 [-], 150108562950transposase B-like protein 
35HPAG1_0526549878..550033 [-], 156108562951transposase B-like protein 
 
Region 2: 1431707..1432237
#Locus tag (Gene)Coordinates [+/-], size (bp)Protein GIProductComponent
1HPAG1_1378 (trmE)1427104..1428489 [+], 1386108563803tRNA modification GTPase TrmE 
2HPAG1_13791428703..1430943 [+], 2241108563804outer membrane protein HomD 
3HPAG1_13801431072..1431218 [-], 147108563805hypothetical protein 
4HPAG1_13811431375..1431626 [+], 252108563806MobC-like protein 
5HPAG1_13821431707..1432237 [+], 531108563807cagY like protein  CagY
6HPAG1_1383 (thyX)1432271..1432897 [-], 627108563808FAD-dependent thymidylate synthase 
7HPAG1_13841432919..1434712 [-], 1794108563809glucosamine--fructose-6-phosphate aminotransferase 
8HPAG1_13851434713..1434952 [-], 240108563810hypothetical protein 
9HPAG1_13861434995..1435537 [-], 543108563811purine nucleoside phosphorylase 
10HPAG1_1387 (dnaA)1435690..1437057 [+], 1368108563812chromosomal replication initiation protein 
 
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  *
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) (108562943)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 (108562949)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 (108562949)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 (108562949)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 (108562949)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 (108562949)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 (108562949)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 (108562949)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 (108562949)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 (108562949)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: 20478541insolico
10CagA (108562949)c-Abl tyrosine kinasehumanCagA directly targets to c-Abl and localizes in in focal adhesion complexes and membrane ruffles.(10) PubMed: 17160020insolico
11CagA (108562949)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 (108562949)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 (108562949)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 (108562949)unknownhumanCagA promotes the proliferation and inhibits the apoptosis of GES-1 cells via upregulated TRAF1/4-1BB.(14) PubMed: 28627614insolico
15CagA (108562949)Adapter molecule crkhumanCagA binding Crk adaptor proteins is important for Helicobacter pylori-induced loss of gastric epithelial cell adhesion.(15) PubMed: 16275761insolico
16CagA (108562949)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 (108562949)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 (108562949)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 (108562939)integrin αvβ5humanCagL/integrin β5 signalling complex is important for H pylori induced gastrin expression.(19) PubMed: 22287591insolico
20CagL (108562939)integrin αvβ6humanαvβ6 is a specific, high affinity receptor for CagL.(20) PubMed: 31197920insolico

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) 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
(20) 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) 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
 
experimental This literature contains experimental investigation
in_silico This literature contains bioinformatics investigation