T4SS ID	37
Strain	Helicobacter pylori HPAG1
Replicon	chromosome [Browse all T4SS(s) in this replicon]
Accession	NC_008086
Location	514158..545246; 1431707..1432237
Name	Cag
Function	effector translocation
Classification	Type IVA; Type P
Bioinformatics investigation has been performed on this T4SS.

T4SS components

Component	CagC	CagD	CagE	CagF	CagG	CagH	CagI	CagL	CagN
Number	1	1	2	1	1	1	1	1	1
Component	CagM	CagT	CagU	CagV	CagW	CagX	CagY	CagZ	Cagalpha
Number	1	1	1	1	1	1	3	1	1
Component	Cagbeta	Caggamma	Cagdelta
Number	1	1	1

The information of T4SS components from NC_008086
Region 1: 514158..545246
#	Locus tag (Gene)	Coordinates [+/-], size (bp)	Protein GI	Product	Component
1	HPAG1_0491 (era)	509873..510778 [+], 906	108562916	GTP-binding protein Era
2	HPAG1_0492	510775..511767 [+], 993	108562917	hypothetical protein
3	HPAG1_0493	511846..512700 [-], 855	108562918	hypothetical protein
4	HPAG1_0494	512719..512958 [+], 240	108562919	IS606 transposase
5	HPAG1_0495	513044..513391 [+], 348	108562920	cag pathogenicity island protein 1
6	HPAG1_0496	513407..514165 [+], 759	108562921	HP0521B-like protein
7	HPAG1_0497	514158..515603 [+], 1446	108562922	cag pathogenicity island protein 3	Cagdelta
8	HPAG1_0498	515613..516122 [+], 510	108562923	cag pathogenicity island protein 4	Caggamma
9	HPAG1_0499	516241..518487 [-], 2247	108562924	cag pathogenicity island protein 5	Cagbeta
10	HPAG1_0500	518496..519488 [-], 993	108562925	cag pathogenicity island encoded protein/ATPase protein	Cagalpha
11	HPAG1_0501	519493..520092 [-], 600	108562926	cag pathogenicity island protein Z	CagZ
12	HPAG1_0502	520227..524114 [-], 3888	108562927	cag pathogenicity island protein Y	CagY
13	HPAG1_0503	524173..526161 [-], 1989	108562928	cag pathogenicity island protein Y	CagY
14	HPAG1_0504	526176..527747 [-], 1572	108562929	cag pathogenicity island protein X	CagX
15	HPAG1_0505	527797..529404 [-], 1608	108562930	cag pathogenicity island protein W	CagW
16	HPAG1_0506	529409..530167 [-], 759	108562931	cag pathogenicity island protein V	CagV
17	HPAG1_0507	530565..531215 [+], 651	108562932	cag pathogenicity island protein U	CagU
18	HPAG1_0508	531228..532070 [+], 843	108562933	cag pathogenicity island protein T	CagT
19	HPAG1_0510	532270..532869 [-], 600	108562935	cag pathogenicity island protein S
20	HPAG1_0511	533301..533681 [-], 381	108562936	cag pathogenicity island protein Q
21	HPAG1_0512	534882..536012 [+], 1131	108562937	cag pathogenicity island protein M	CagM
22	HPAG1_0513	536027..536947 [+], 921	108562938	cag pathogenicity island protein N	CagN
23	HPAG1_0514	537029..537742 [-], 714	108562939	cag pathogenicity island protein L	CagL
24	HPAG1_0515	537739..538884 [-], 1146	108562940	cag pathogenicity island protein I	CagI
25	HPAG1_0516	538895..540007 [-], 1113	108562941	cag pathogenicity island protein H	CagH
26	HPAG1_0517	540024..540452 [-], 429	108562942	cag pathogenicity island protein G	CagG
27	HPAG1_0518	540507..541313 [-], 807	108562943	cag pathogenicity island protein F	CagF
28	HPAG1_0519	541315..542631 [-], 1317	108562944	cag pathogenicity island protein E	CagE
29	HPAG1_0520	542661..544265 [-], 1605	108562945	cag pathogenicity island protein E	CagE
30	HPAG1_0521	544274..544924 [-], 651	108562946	cag pathogenicity island protein D	CagD
31	HPAG1_0522	544899..545246 [-], 348	108562947	cag pathogenicity island protein C	CagC
32	HPAG1_0523	545391..545618 [-], 228	108562948	cag pathogenicity island protein B
33	HPAG1_0524	546049..549651 [+], 3603	108562949	cytotoxin-associated protein A
34	HPAG1_0525	549714..549863 [-], 150	108562950	transposase B-like protein
35	HPAG1_0526	549878..550033 [-], 156	108562951	transposase B-like protein
Region 2: 1431707..1432237
#	Locus tag (Gene)	Coordinates [+/-], size (bp)	Protein GI	Product	Component
1	HPAG1_1378 (trmE)	1427104..1428489 [+], 1386	108563803	tRNA modification GTPase TrmE
2	HPAG1_1379	1428703..1430943 [+], 2241	108563804	outer membrane protein HomD
3	HPAG1_1380	1431072..1431218 [-], 147	108563805	hypothetical protein
4	HPAG1_1381	1431375..1431626 [+], 252	108563806	MobC-like protein
5	HPAG1_1382	1431707..1432237 [+], 531	108563807	cagY like protein	CagY
6	HPAG1_1383 (thyX)	1432271..1432897 [-], 627	108563808	FAD-dependent thymidylate synthase
7	HPAG1_1384	1432919..1434712 [-], 1794	108563809	glucosamine--fructose-6-phosphate aminotransferase
8	HPAG1_1385	1434713..1434952 [-], 240	108563810	hypothetical protein
9	HPAG1_1386	1434995..1435537 [-], 543	108563811	purine nucleoside phosphorylase
10	HPAG1_1387 (dnaA)	1435690..1437057 [+], 1368	108563812	chromosomal replication initiation protein

 This T4SS contains information of accessory protein.
 This T4SS contains information of interaction.

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 GI	Product	*
1	HPAG1_0524	546049..549651 [+], 3603	108562949	cytotoxin-associated protein A	CagA

 T4SE derived from experimental literature.
 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)	Function	Reference
1	CagF (chaperone) (108562943)	CT20aa and an intact N terminus	CagA	The 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]

The information on host-pathogen interaction.

#	Name(Protein GI)	Host site/Substrate	Source	Function	Reference
1	CagA (108562949)	SHP-2	human	CagA is translocated into gastric epithelial cells. It physically interacts with SHP-2 to modify cellular functions and perturb mammalian signal transduction machineries. This may induce gastric epithelial cells to move and proliferate abnormally and help to acquire a cellular transformed phenotype.	(1) PubMed: 11743164
2	CagA (108562949)	growth factor receptor bound 2 (Grb2)	unknown	CagA targets to Grb2 and this process leads to activing the MEK/ERK pathway and results in cell scattering and proliferation.	(2) PubMed: 12419219
3	CagA (108562949)	PAR1/MARK kinase	human	CagA interacts with PAR1/MARK kinase to inhibit the activity of PAR1 kinase and prevent PAR1 phosphorylation which mediated by atypical protein kinase C (aPKC).	(3) PubMed: 17507984
4	CagA (108562949)	Apoptosis-stimulating of p53 protein 2 (ASPP2)	human	ASPP2 is a tumor suppressor that activates the apoptotic response upon cellular stress which mediated by p53. CagA interacts with ASPP2 to change the function of ASPP2 and this process leads to the decreased survival of cells which infected by H. pylori.	(4) PubMed: 24474782
5	CagA (108562949)	protein kinase C-related kinase 2 (PRK2)	human	CagA represses kinase activity of PRK2, which has been involved in establishment of cell polarity and rearrangements of cytoskeleton, to further control signalling pathways associated with cancer.	(5) PubMed: 26041307
6	CagA (108562949)	Glycogen synthase kinase 3 (GSK-3)	human	CagA interacts with GSK-3 to reduce its activity by cause it to transform into an insoluble fraction. CagA then induce a epithelial mesenchymal transition mediated by Snail via the comsuming of GSK-3.	(6) PubMed: 25055241
7	CagA (108562949)	c-Met	human	CagA interacts with the c-Met receptor to modulates cellular functions through deregulating c-Met receptor signaling and participates in invasive growth of tumor cells.	(7) PubMed: 12719469
8	CagA (108562949)	E-cadherin	human	CagA interacts with E-cadherin to impair the complex formation between E-cadherin and beta-catenin and facilitate transdifferentiation of intestines in gastric epithelial cells.	(8) PubMed: 17237808
9	CagA (108562949)	host membrane phosphatidylserine	unknown	CagA can be tethered to the inner leaflet of the plasma membrane by interacting with phosphatidylserine. Then it binds the PAR1/MARK to induce polarity and junctional defects.	(9) PubMed: 20478541
10	CagA (108562949)	c-Abl tyrosine kinase	human	CagA targets to c-Abl directly and localizes in focal adhesion complexes and membrane ruffles.	(10) PubMed: 17160020
11	CagA (108562949)	αPix	human	CagA interacted with αPix to activates PAK1, ERK and NF-kappaB after being delivered into AGS cells. Then it induces the expression of IL-8 in infected gastric epithelial cells.	(11) PubMed: 19672789
12	CagA (108562949)	scaffolding protein ZO-1	human, canine	CagA interacts with epithelial tight-junction ZO-1 and the transmembrane protein junctional adhesion molecule to change the function and composition of the apical-junctional complex.	(12) PubMed: 12775840
13	CagA (108562949)	integrin α5β1 receptor	human	CagA binds interface with α5β1 integrin.It is an essential step for the translocation process of CagA into the host cell.	(13) PubMed: 22908298
14	CagA (108562949)	unknown	human	CagA facilitates the proliferation and represses the apoptosis of GES-1 cells by upregulated TRAF1/4-1BB.	(14) PubMed: 28627614
15	CagA (108562949)	Adapter molecule crk	human	The interaction between CagA and Crk adaptor proteins is important for loss of gastric epithelial cell adhesion induced by Helicobacter pylori-induced Helicobacter pylori.	(15) PubMed: 16275761
16	CagA (108562949)	SHP-1	human	CagA interacts with SHP1 to enhance the phosphatase activity of SHP1 so that it dampens the oncogenic action of CagA.	(16) PubMed: 27572445
17	CagA (108562949)	Transforming growth factor-beta-activated kinase 1 (TAK1)	human	CagA interacts with TAK1 and improves its activity to activate NF-kappaB through the ubiquitination of TAK1.	(17) PubMed: 19820695
18	CagA (108562949)	Myeloid cell leukemia sequence-1 (MCL1)	mongolian gerbil	CagA increases MCL1 thorough the interaction between SRE/SRF and CagA/MCL1 in modulating rapid turnover of pit epithelial cells via MEK/ERK/SRE activation.	(18) PubMed: 18005743
19	CagL (108562939)	integrin αvβ5	human	CagL/integrin β5 signalling complex is important for gastrin expression induced by H. pylori.	(19) PubMed: 22287591
20	CagL (108562939)	integrin αvβ6	human	αvβ6 is a specific, high affinity receptor for CagL.	(20) PubMed: 31197920

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]

(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]

(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]

(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]

(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]

(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]

(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]

(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]

(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]

(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]

(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]

(12) Amieva MR et al. (2003). Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 300(5624):1430-4. [PudMed:12775840]

(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]

(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]

(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]

(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]

(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]

(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]

(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]

(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]

(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]

(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]

This literature contains experimental investigation

This literature contains bioinformatics investigation