{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T03:20:21Z","timestamp":1784172021866,"version":"3.55.0"},"reference-count":85,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2017,4,13]],"date-time":"2017-04-13T00:00:00Z","timestamp":1492041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MEXT KAKENHI","award":["25250016"],"award-info":[{"award-number":["25250016"]}]},{"DOI":"10.13039\/501100003382","name":"CREST","doi-asserted-by":"publisher","award":["120200000396"],"award-info":[{"award-number":["120200000396"]}],"id":[{"id":"10.13039\/501100003382","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>CagA, an oncogenic virulence factor produced by Helicobacter pylori, is causally associated with the development of gastrointestinal diseases such as chronic gastritis, peptic ulcers, and gastric cancer. Upon delivery into gastric epithelial cells via bacterial type IV secretion, CagA interacts with a number of host proteins through the intrinsically disordered C-terminal tail, which contains two repeatable protein-binding motifs, the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif and the CagA multimerization (CM) motif. The EPIYA motif, upon phosphorylation by host kinases, binds and deregulates Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2), a bona fide oncoprotein, inducing pro-oncogenic mitogenic signaling and abnormal cell morphology. Through the CM motif, CagA inhibits the kinase activity of polarity regulator partitioning-defective 1b (PAR1b), causing junctional and polarity defects while inducing actin cytoskeletal rearrangements. The magnitude of the pathobiological action of individual CagA has been linked to the tandem repeat polymorphisms of these two binding motifs, yet the molecular mechanisms by which they affect disease outcome remain unclear. Recent studies using quantitative techniques have provided new insights into how the sequence polymorphisms in the structurally disordered C-terminal region determine the degree of pro-oncogenic action of CagA in the gastric epithelium.<\/jats:p>","DOI":"10.3390\/toxins9040136","type":"journal-article","created":{"date-parts":[[2017,4,13]],"date-time":"2017-04-13T10:55:44Z","timestamp":1492080944000},"page":"136","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Sequence Polymorphism and Intrinsic Structural Disorder as Related to Pathobiological Performance of the Helicobacter pylori CagA Oncoprotein"],"prefix":"10.3390","volume":"9","author":[{"given":"Hiroko","family":"Nishikawa","sequence":"first","affiliation":[{"name":"Division of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan"},{"name":"CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan"},{"name":"Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Hatakeyama","sequence":"additional","affiliation":[{"name":"Division of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan"},{"name":"CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan"},{"name":"Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1056\/NEJMoa001999","article-title":"Helicobacter pylori infection and the development of gastric cancer","volume":"345","author":"Uemura","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1056\/NEJM199110173251603","article-title":"Helicobacter pylori infection and the risk of gastric carcinoma","volume":"325","author":"Parsonnet","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/nrc703","article-title":"Helicobacter pylori and gastrointestinal tract adenocarcinomas","volume":"2","author":"Peek","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"E359","DOI":"10.1002\/ijc.29210","article-title":"Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012","volume":"136","author":"Ferlay","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1097\/00042737-199806000-00007","article-title":"Topographic distribution of Helicobacter pylori in the resected stomach","volume":"10","author":"Enomoto","year":"1998","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/nrc1433","article-title":"Oncogenic mechanisms of the Helicobacter pylori CagA protein","volume":"4","author":"Hatakeyama","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7047","DOI":"10.1038\/onc.2008.353","article-title":"Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA","volume":"27","author":"Hatakeyama","year":"2008","journal-title":"Oncogene"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1111\/cmi.12040","article-title":"Bacterial EPIYA effectors\u2014Where do they come from? What are they? Where are they going?","volume":"15","author":"Hayashi","year":"2013","journal-title":"Cell. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.chom.2014.02.008","article-title":"Helicobacter pylori CagA and gastric cancer: A paradigm for hit-and-run carcinogenesis","volume":"15","author":"Hatakeyama","year":"2014","journal-title":"Cell Host Microbe"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14648","DOI":"10.1073\/pnas.93.25.14648","article-title":"cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors","volume":"93","author":"Censini","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1046\/j.1365-2958.1998.00770.x","article-title":"Analyses of the cag pathogenicity island of Helicobacter pylori","volume":"28","author":"Akopyants","year":"1998","journal-title":"Mol. Microbiol."},{"key":"ref_12","first-page":"2111","article-title":"Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach","volume":"55","author":"Blaser","year":"1995","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1136\/gut.40.3.297","article-title":"Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection","volume":"40","author":"Parsonnet","year":"1997","journal-title":"Gut"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.chom.2012.05.010","article-title":"Tertiary structure-function analysis reveals the pathogenic signaling potentiation mechanism of Helicobacter pylori oncogenic effector CagA","volume":"12","author":"Hayashi","year":"2012","journal-title":"Cell Host Microbe"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14640","DOI":"10.1073\/pnas.1206098109","article-title":"Structural insights into Helicobacter pylori oncoprotein CagA interaction with \u03b21 integrin","volume":"109","author":"Dian","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Woon, A.P., Tohidpour, A., Alonso, H., Saijo-Hamano, Y., Kwok, T., and Roujeinikova, A. (2013). Conformational analysis of isolated domains of Helicobacter pylori CagA. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079367"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.sbi.2015.08.009","article-title":"Intrinsically disordered proteins: Emerging interaction specialists","volume":"35","author":"Tompa","year":"2015","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/nrm3920","article-title":"Intrinsically disordered proteins in cellular signalling and regulation","volume":"16","author":"Wright","year":"2015","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1016\/j.cell.2015.05.024","article-title":"SnapShot: Intrinsic structural disorder","volume":"161","author":"Guharoy","year":"2015","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.sbi.2016.10.015","article-title":"Intrinsically disordered proteins in overcrowded milieu: Membrane-less organelles, phase separation, and intrinsic disorder","volume":"44","author":"Uversky","year":"2016","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6775","DOI":"10.1074\/jbc.C100754200","article-title":"Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo","volume":"277","author":"Selbach","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1046\/j.1365-2958.2002.02781.x","article-title":"c-Src\/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs","volume":"43","author":"Stein","year":"2002","journal-title":"Mol. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"32344","DOI":"10.1074\/jbc.M606172200","article-title":"Structural basis and functional consequence of Helicobacter pylori CagA multimerization in cells","volume":"281","author":"Ren","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.1523-5378.2010.00759.x","article-title":"The versatility of Helicobacter pylori CagA effector protein functions: The master key hypothesis","volume":"15","author":"Backert","year":"2010","journal-title":"Helicobacter"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.chom.2010.04.005","article-title":"Helicobacter pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of the CagA oncoprotein","volume":"7","author":"Kikuchi","year":"2010","journal-title":"Cell Host Microbe"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1126\/science.1067147","article-title":"SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein","volume":"295","author":"Higashi","year":"2002","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3664","DOI":"10.1074\/jbc.M208155200","article-title":"Attenuation of Helicobacter pylori CagA\u00b7SHP-2 signaling by interaction between CagA and C-terminal Src kinase","volume":"278","author":"Tsutsumi","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1084\/jem.20051027","article-title":"Interaction of CagA with Crk plays an important role in Helicobacter pylori\u2013induced loss of gastric epithelial cell adhesion","volume":"202","author":"Suzuki","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nature05765","article-title":"Helicobacter pylori CagA targets PAR1\/MARK kinase to disrupt epithelial cell polarity","volume":"447","author":"Saadat","year":"2007","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/nsmb.1705","article-title":"Helicobacter pylori CagA inhibits PAR1-MARK family kinases by mimicking host substrates","volume":"17","author":"Miller","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14428","DOI":"10.1073\/pnas.222375399","article-title":"Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites","volume":"99","author":"Higashi","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Furuta, Y., Yahara, K., Hatakeyama, M., and Kobayashi, I. (2011). Evolution of cagA oncogene of Helicobacter pylori through recombination. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023499"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/S0968-0004(03)00091-4","article-title":"The \u201cShp\u201ding news: SH2 domain-containing tyrosine phosphatases in cell signaling","volume":"28","author":"Neel","year":"2003","journal-title":"Trends Biochem. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/S0092-8674(00)80938-1","article-title":"Crystal structure of the tyrosine phosphatase SHP-2","volume":"92","author":"Hof","year":"1998","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"21244","DOI":"10.1016\/S0021-9258(17)31955-5","article-title":"Syp (SH-PTP2) is a positive mediator of growth factor-stimulated mitogenic signal transduction","volume":"269","author":"Xiao","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1073\/pnas.92.3.664","article-title":"Protein-tyrosine-phosphatase SHPTP2 is a required positive effector for insulin downstream signaling","volume":"92","author":"Yamauchi","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s10555-008-9126-y","article-title":"The tyrosine phosphatase Shp2 (PTPN11) in cancer","volume":"27","author":"Chan","year":"2008","journal-title":"Cancer Metastasis Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1097\/00043426-199911000-00014","article-title":"Juvenile myelomonocytic leukemia and Noonan syndrome","volume":"21","author":"Choong","year":"1999","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/ng772","article-title":"Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome","volume":"29","author":"Tartaglia","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1182\/blood-2003-09-3287","article-title":"Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis","volume":"103","author":"Loh","year":"2004","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/ng1156","article-title":"Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia","volume":"34","author":"Tartaglia","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1073\/pnas.0711183105","article-title":"Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse","volume":"105","author":"Ohnishi","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1002\/ijc.24740","article-title":"Differential oncogenic potential of geographically distinct Helicobacter pylori CagA isoforms in mice","volume":"125","author":"Miura","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Xia, Y., Yamaoka, Y., Zhu, Q., Matha, I., and Gao, X. (2009). A comprehensive sequence and disease correlation analyses for the C-terminal region of CagA protein of Helicobacter pylori. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007736"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Karlsson, A., Ryberg, A., Dehnoei, M., Borch, K., and Monstein, H.-J. (2012). Association between cagA and vacA genotypes and pathogenesis in a Helicobacter pylori infected population from South-eastern Sweden. BMC Microbiol., 12.","DOI":"10.1186\/1471-2180-12-129"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Nagase, L., Hayashi, T., Senda, T., and Hatakeyama, M. (2015). Dramatic increase in SHP2 binding activity of Helicobacter pylori Western CagA by EPIYA-C duplication: Its implications in gastric carcinogenesis. Sci. Rep.","DOI":"10.1038\/srep15749"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Nishikawa, H., Hayashi, T., Arisaka, F., Senda, T., and Hatakeyama, M. (2016). Impact of structural polymorphism for the Helicobacter pylori CagA oncoprotein on binding to polarity-regulating kinase PAR1b. Sci. Rep., 6.","DOI":"10.1038\/srep30031"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0092-8674(88)80024-2","article-title":"Identification of genes required for cytoplasmic localization in early C. elegans embryos","volume":"52","author":"Kemphues","year":"1988","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7679","DOI":"10.1074\/jbc.270.13.7679","article-title":"Microtubule-associated protein\/microtubule affinity-regulating kinase (p110mark): A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262","volume":"270","author":"Drewes","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0092-8674(00)80208-1","article-title":"MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption","volume":"89","author":"Drewes","year":"1997","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/S0960-9822(06)00260-0","article-title":"Mammalian homologues of C. elegans PAR-1 are asymmetrically localized in epithelial cells and may influence their polarity","volume":"7","author":"Brinkmann","year":"1997","journal-title":"Curr. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.cub.2004.04.007","article-title":"Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity","volume":"14","author":"Hurov","year":"2004","journal-title":"Curr. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/j.cub.2004.08.021","article-title":"aPKC acts upstream of PAR-1b in both the establishment and maintenance of mammalian epithelial polarity","volume":"14","author":"Suzuki","year":"2004","journal-title":"Curr. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1111\/j.1349-7006.2008.00950.x","article-title":"Structural and functional diversity in the PAR1b\/MARK2-binding region of Helicobacter pylori CagA","volume":"99","author":"Lu","year":"2008","journal-title":"Cancer Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1111\/j.1462-5822.2007.01084.x","article-title":"Analysis of detergent-resistant membranes of Helicobacter pylori infected gastric adenocarcinoma cells reveals a role for MARK2\/Par1b in CagA-mediated disruption of cellular polarity","volume":"10","author":"Zeaiter","year":"2008","journal-title":"Cell. Microbiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"44576","DOI":"10.1074\/jbc.M111.267021","article-title":"Polarity-regulating kinase partitioning-defective 1b (PAR1b) phosphorylates guanine nucleotide exchange factor H1 (GEF-H1) to regulate RhoA-dependent actin cytoskeletal reorganization","volume":"286","author":"Yamahashi","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Kersulyte, D., Kalia, A., Gilman, R.H., Mendez, M., Herrera, P., Cabrera, L., Velapati\u00f1o, B., Balqui, J., Paredes Puente de la Vega, F., and Rodriguez Ulloa, C.A. (2010). Helicobacter pylori from Peruvian Amerindians: Traces of human migrations in strains from remote Amazon, and genome sequence of an Amerind strain. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015076"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3078","DOI":"10.1128\/JB.00063-10","article-title":"Host-interactive genes in Amerindian Helicobacter pylori diverge from their old world homologs and mediate inflammatory responses","volume":"192","author":"Mane","year":"2010","journal-title":"J. Bacteriol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"29964","DOI":"10.1074\/jbc.M111.263715","article-title":"Attenuated CagA oncoprotein in Helicobacter pylori from Amerindians in Peruvian Amazon","volume":"286","author":"Suzuki","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/cas.12342","article-title":"Natural variant of the Helicobacter pylori CagA oncoprotein that lost the ability to interact with PAR1","volume":"105","author":"Hashi","year":"2014","journal-title":"Cancer Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1111\/j.1742-4658.2010.07655.x","article-title":"Cytoskeleton-modulating effectors of enteropathogenic and enterohemorrhagic Escherichia coli: A case for EspB as an intrinsically less-ordered effector","volume":"277","author":"Hamada","year":"2010","journal-title":"FEBS J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nrm1589","article-title":"Intrinsically unstructured proteins and their functions","volume":"6","author":"Dyson","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6573","DOI":"10.1021\/bi012159+","article-title":"Intrinsic disorder and protein function","volume":"41","author":"Dunker","year":"2002","journal-title":"Biochemistry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0022-2836(02)00969-5","article-title":"Intrinsic disorder in cell-signaling and cancer-associated proteins","volume":"323","author":"Iakoucheva","year":"2002","journal-title":"J. Mol. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.pbiomolbio.2008.05.007","article-title":"Intrinsic disorder in scaffold proteins: Getting more from less","volume":"98","author":"Cortese","year":"2008","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/bies.10324","article-title":"Intrinsically unstructured proteins evolve by repeat expansion","volume":"25","author":"Tompa","year":"2003","journal-title":"BioEssays"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.tim.2005.08.002","article-title":"Tyrosine-phosphorylated bacterial effector proteins: The enemies within","volume":"13","author":"Backert","year":"2005","journal-title":"Trends Microbiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1529\/biophysj.106.101766","article-title":"Conformation of the EPEC Tir protein in solution: Investigating the impact of serine phosphorylation at positions 434\/463","volume":"93","author":"Race","year":"2007","journal-title":"Biophys. J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1039\/C1MB05272A","article-title":"Order and disorder in large multi-site docking proteins of the Gab family\u2014Implications for signalling complex formation and inhibitor design strategies","volume":"8","author":"Simister","year":"2012","journal-title":"Mol. BioSyst."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1074\/jbc.M116.747485","article-title":"Biophysical evidence for intrinsic disorder in the C-terminal tails of the epidermal growth factor receptor (EGFR) and HER3 receptor tyrosine kinases","volume":"292","author":"Keppel","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Lippens, G., Landrieu, I., Smet, C., Huvent, I., Gandhi, N.S., Gigant, B., Despres, C., Qi, H., and Lopez, J. (2016). NMR meets tau: Insights into its function and pathology. Biomolecules, 6.","DOI":"10.3390\/biom6020028"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0166-2236(91)90105-4","article-title":"Molecular characterization of microtubule-associated proteins tau and MAP2","volume":"14","author":"Goedert","year":"1991","journal-title":"Trends Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Dehmelt, L., and Halpain, S. (2005). The MAP2\/Tau family of microtubule-associated proteins. Genome Biol., 6.","DOI":"10.1186\/gb-2004-6-1-204"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"9068","DOI":"10.1021\/bi401266n","article-title":"Phosphorylation of human tau protein by microtubule affinity-regulating kinase 2","volume":"52","author":"Schwalbe","year":"2013","journal-title":"Biochemistry"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/0896-6273(93)90279-Z","article-title":"Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: Distinction between PHF-like immunoreactivity and microtubule binding","volume":"11","author":"Biernat","year":"1993","journal-title":"Neuron"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1006\/abbi.1998.0813","article-title":"Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules","volume":"357","author":"Sengupta","year":"1998","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"18917","DOI":"10.1074\/jbc.270.32.18917","article-title":"Detection of phosphorylated Ser262 in fetal tau, adult tau, and paired helical filament tau","volume":"270","author":"Seubert","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Sievers, F., Wilm, A., Dineen, D., Gibson, T.J., Karplus, K., Li, W., Lopez, R., McWilliam, H., Remmert, M., and S\u00f6ding, J. (2011). Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol. Syst. Biol., 7.","DOI":"10.1038\/msb.2011.75"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Mohan, A., Sullivan, W.J., Radivojac, P., Dunker, A.K., and Uversky, V.N. (2008). Intrinsic disorder in pathogenic and non-pathogenic microbes: Discovering and analyzing the unfoldomes of early-branching eukaryotes. Mol. Biosyst., 4.","DOI":"10.1039\/b719168e"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6880","DOI":"10.1021\/cr4005692","article-title":"Structural disorder in viral proteins","volume":"114","author":"Xue","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Shimoda, A., Ueda, K., Nishiumi, S., Murata-Kamiya, N., Mukai, S., Sawada, S., Azuma, T., Hatakeyama, M., and Akiyoshi, K. (2016). Exosomes as nanocarriers for systemic delivery of the Helicobacter pylori virulence factor CagA. Sci. Rep., 6.","DOI":"10.1038\/srep18346"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1161\/01.CIR.97.17.1675","article-title":"Association of virulent Helicobacter pylori strains with ischemic heart disease","volume":"97","author":"Pasceri","year":"1998","journal-title":"Circulation"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1046\/j.1365-2141.2003.04735.x","article-title":"Molecular mimicry by Helicobacter pylori CagA protein may be involved in the pathogenesis of H. pylori-associated chronic idiopathic thrombocytopenic purpura","volume":"124","author":"Takahashi","year":"2004","journal-title":"Br. J. Haematol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1097\/HJH.0b013e3280109e8c","article-title":"Pre-eclampsia is associated with Helicobacter pylori seropositivity in Italy","volume":"24","author":"Ponzetto","year":"2006","journal-title":"J. Hypertens."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.clineuro.2009.11.008","article-title":"Could Helicobacter pylori play an important role in axonal type of Guillain-Barr\u00e9 Syndrome pathogenesis?","volume":"112","author":"Ghabaee","year":"2010","journal-title":"Clin. Neurol. Neurosurg."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/9\/4\/136\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:32:37Z","timestamp":1760207557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/9\/4\/136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,13]]},"references-count":85,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2017,4]]}},"alternative-id":["toxins9040136"],"URL":"https:\/\/doi.org\/10.3390\/toxins9040136","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,13]]}}}