{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:21:36Z","timestamp":1788344496179,"version":"build-2803163510"},"reference-count":41,"publisher":"American Chemical Society (ACS)","issue":"2","license":[{"start":{"date-parts":[[2015,12,22]],"date-time":"2015-12-22T00:00:00Z","timestamp":1450742400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM082892"],"award-info":[{"award-number":["GM082892"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["F30DK091978"],"award-info":[{"award-number":["F30DK091978"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,1,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Rho family GTPases modulate actin cytoskeleton dynamics by signaling through multiple effectors, including the p21-activated kinases (PAKs). The intestinal parasite Entamoeba histolytica expresses \u223c20 Rho family GTPases and seven isoforms of PAK, two of which have been implicated in pathogenesis-related processes such as amoebic motility and invasion and host cell phagocytosis. Here, we describe two previously unstudied PAK isoforms, EhPAK4 and EhPAK5, as highly specific effectors of EhRacC. A structural model based on 2.35 \u00c5 X-ray crystallographic data of a complex between EhRacCQ65L\u00b7GTP and the EhPAK4 p21 binding domain (PBD) reveals a fairly well-conserved Rho\/effector interface despite deviation of the PBD \u03b1-helix. A structural comparison with EhRho1 in complex with EhFormin1 suggests likely determinants of Rho family GTPase signaling specificity in E. histolytica. These findings suggest a high degree of Rho family GTPase diversity and specificity in the single-cell parasite E. histolytica. Because PAKs regulate pathogenesis-related processes in E. histolytica, they may be valid pharmacologic targets for anti-amoebiasis drugs.<\/jats:p>","DOI":"10.1021\/bi501226f","type":"journal-article","created":{"date-parts":[[2014,12,22]],"date-time":"2014-12-22T00:32:10Z","timestamp":1419208330000},"page":"404-412","source":"Crossref","is-referenced-by-count":9,"title":["<i>Entamoeba histolytica<\/i>\n                    RacC Selectively\nEngages p21-Activated Kinase Effectors"],"prefix":"10.1021","volume":"54","author":[{"given":"Dustin E.","family":"Bosch","sequence":"first","affiliation":[{"name":"The University of North Carolina , , , ,","place":["Chapel Hill, North Carolina, United States, 27514"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P.","family":"Siderovski","sequence":"additional","affiliation":[{"name":"West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center , , , ,","place":["Morgantown, West Virginia, United States, 26506"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,12,22]]},"reference":[{"key":"2026090206114461000_cit1","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1098\/rstb.2000.0632","article-title":"Rho GTPases:\nMolecular switches that control the organization\nand dynamics of the actin cytoskeleton","volume":"355","author":"Hall","year":"2000","journal-title":"Philos.\nTrans. R. Soc. London"},{"key":"2026090206114461000_cit2","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1242\/jcs.01118","article-title":"Rho-family GTPases: It\u2019s not only Rac and Rho\n(and I like it)","volume":"117","author":"Wennerberg","year":"2004","journal-title":"J. Cell Sci."},{"key":"2026090206114461000_cit3","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/35047014","article-title":"Crystal structure\nof Rac1 in complex\nwith the guanine nucleotide exchange region of Tiam1","volume":"408","author":"Worthylake","year":"2000","journal-title":"Nature"},{"key":"2026090206114461000_cit4","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/nrc2960","article-title":"Ras superfamily\nGEFs and GAPs: Validated and tractable targets for cancer therapy?","volume":"10","author":"Vigil","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"2026090206114461000_cit5","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1042\/BC20070109","article-title":"A tale of two Paks","volume":"100","author":"Arias-Romero","year":"2008","journal-title":"Biol. Cell"},{"key":"2026090206114461000_cit6","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/embor.2012.75","article-title":"Group I and\nII mammalian PAKs have different modes of activation by Cdc42","volume":"13","author":"Baskaran","year":"2012","journal-title":"EMBO Rep."},{"key":"2026090206114461000_cit7","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0092-8674(00)00043-X","article-title":"Structure of PAK1 in an autoinhibited conformation\nreveals a multistage activation switch","volume":"102","author":"Lei","year":"2000","journal-title":"Cell"},{"key":"2026090206114461000_cit8","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/onc.2011.294","article-title":"A Rac1\/PAK1\ncascade controls \u03b2-catenin activation\nin colon cancer cells","volume":"31","author":"Zhu","year":"2012","journal-title":"Oncogene"},{"key":"2026090206114461000_cit9","doi-asserted-by":"crossref","first-page":"6023","DOI":"10.1128\/MCB.22.17.6023-6033.2002","article-title":"Rac-PAK signaling\nstimulates extracellular signal-regulated kinase (ERK) activation\nby regulating formation of MEK1-ERK complexes","volume":"22","author":"Eblen","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"2026090206114461000_cit10","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1517\/14728222.2010.492779","article-title":"PAK1 as a therapeutic\ntarget","volume":"14","author":"Kichina","year":"2010","journal-title":"Expert Opin. Ther. Targets"},{"key":"2026090206114461000_cit11","doi-asserted-by":"crossref","first-page":"491","DOI":"10.18632\/oncotarget.271","article-title":"p21-activated\nkinase 1: PAK\u2019ed with potential","volume":"2","author":"Ong","year":"2011","journal-title":"Oncotarget"},{"key":"2026090206114461000_cit12","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.chembiol.2008.03.005","article-title":"An isoform-selective,\nsmall-molecule inhibitor targets the autoregulatory mechanism of p21-activated\nkinase","volume":"15","author":"Deacon","year":"2008","journal-title":"Chem. 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Immun."},{"key":"2026090206114461000_cit20","doi-asserted-by":"crossref","first-page":"39236","DOI":"10.1074\/jbc.M111.253898","article-title":"Unique\nstructural and nucleotide exchange features of the Rho1 GTPase of Entamoeba histolytica","volume":"286","author":"Bosch","year":"2011","journal-title":"J. Biol.\nChem."},{"key":"2026090206114461000_cit21","doi-asserted-by":"crossref","first-page":"8791","DOI":"10.1021\/bi300954g","article-title":"Entamoeba histolytica Rho1 regulates actin polymerization\nthrough a divergent, diaphanous-related\nformin","volume":"51","author":"Bosch","year":"2012","journal-title":"Biochemistry"},{"key":"2026090206114461000_cit22","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.str.2012.11.012","article-title":"Structural\nDeterminants of RGS-RhoGEF Signaling Critical to Entamoeba histolytica Pathogenesis","volume":"21","author":"Bosch","year":"2013","journal-title":"Structure"},{"key":"2026090206114461000_cit23","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.molbiopara.2006.04.001","article-title":"EhPAK2, a novel p21-activated\nkinase, is required for collagen invasion and capping in Entamoeba histolytica","volume":"149","author":"Arias-Romero","year":"2006","journal-title":"Mol.\nBiochem. Parasitol."},{"key":"2026090206114461000_cit24","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1242\/jcs.00190","article-title":"EhPAK, a member of the p21-activated kinase family,\nis involved in the control of Entamoeba histolytica migration and phagocytosis","volume":"116","author":"Labruyere","year":"2003","journal-title":"J. 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Res."},{"key":"2026090206114461000_cit36","doi-asserted-by":"crossref","first-page":"W545","DOI":"10.1093\/nar\/gkq366","article-title":"Dali server:\nConservation mapping in 3D","volume":"38","author":"Holm","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2026090206114461000_cit37","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/20726","article-title":"Structure of Cdc42 in complex with\nthe GTPase-binding domain of the \u2018Wiskott-Aldrich syndrome\u2019\nprotein","volume":"399","author":"Abdul-Manan","year":"1999","journal-title":"Nature"},{"key":"2026090206114461000_cit38","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/75158","article-title":"Structure of Cdc42 bound to the GTPase\nbinding domain of PAK","volume":"7","author":"Morreale","year":"2000","journal-title":"Nat. Struct. Biol."},{"key":"2026090206114461000_cit39","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/20732","article-title":"Structure\nof the small G protein Cdc42 bound to the\nGTPase-binding domain of ACK","volume":"399","author":"Mott","year":"1999","journal-title":"Nature"},{"key":"2026090206114461000_cit40","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.1021\/bi992646d","article-title":"Structure of the\ncomplex of Cdc42Hs with a peptide derived from P-21 activated kinase","volume":"39","author":"Gizachew","year":"2000","journal-title":"Biochemistry"},{"key":"2026090206114461000_cit41","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3410\/B2-70","article-title":"Do PAKs make good drug targets?","volume":"2","author":"Zhao","year":"2010","journal-title":"F1000 Biology Reports"}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/bi501226f","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/54\/2\/404\/15709116\/bi501226f.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/54\/2\/404\/15709116\/bi501226f.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:11:59Z","timestamp":1788343919000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/54\/2\/404\/1477976\/Entamoeba-histolytica-RacC-Selectively-Engages-p21"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,22]]},"references-count":41,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2014,12,22]]},"published-print":{"date-parts":[[2015,1,20]]}},"URL":"https:\/\/doi.org\/10.1021\/bi501226f","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,22]]}}}