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Article: The unique trimeric assembly of the virulence factor HtrA from Helicobacter pylori occurs via N-terminal domain swapping

TitleThe unique trimeric assembly of the virulence factor HtrA from Helicobacter pylori occurs via N-terminal domain swapping
Authors
Issue Date2019
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal of Biological Chemistry, 2019, v. 294, p. 7990-8000 How to Cite?
AbstractKnowledge of the molecular mechanisms of specific bacterial virulence factors can significantly contribute to antibacterial drug discovery. Helicobacter pylori is a Gram-negative microaerophilic bacterium that infects almost half of the world’s population, leading to gastric disorders and even gastric cancer. H. pylori expresses a series of virulence factors in the host, among which high-temperature requirement A (HpHtrA) is a newly identified serine protease secreted by H. pylori. HpHtrA cleaves the extracellular domain of the epithelial cell surface adhesion protein E-cadherin and disrupts gastric epithelial cell junctions, allowing H. pylori to access the intercellular space. Here we report the first crystal structure of HpHtrA at 3.0 Å resolution. The structure revealed a new type of HtrA protease trimer stabilized by unique N-terminal domain swapping distinct from other known HtrA homologs. We further observed that truncation of the N terminus completely abrogates HpHtrA trimer formation as well as protease activity. In the presence of unfolded substrate, HpHtrA assembled into cage-like 12-mers or 24-mers. Combining crystallographic, biochemical, and mutagenic data, we propose a mechanistic model of how HpHtrA recognizes and cleaves the well-folded E-cadherin substrate. Our study provides a fundamental basis for the development of anti-H. pylori agents by using a previously uncharacterized HtrA protease as a target.
Persistent Identifierhttp://hdl.handle.net/10722/270071
ISSN
2020 Impact Factor: 5.157
2023 SCImago Journal Rankings: 1.766
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhang, ZM-
dc.contributor.authorHuang, Q-
dc.contributor.authorTao, X-
dc.contributor.authorSong, GB-
dc.contributor.authorZheng, P-
dc.contributor.authorLi, H-
dc.contributor.authorSun, H-
dc.contributor.authorXia, W-
dc.date.accessioned2019-05-20T05:08:56Z-
dc.date.available2019-05-20T05:08:56Z-
dc.date.issued2019-
dc.identifier.citationJournal of Biological Chemistry, 2019, v. 294, p. 7990-8000-
dc.identifier.issn0021-9258-
dc.identifier.urihttp://hdl.handle.net/10722/270071-
dc.description.abstractKnowledge of the molecular mechanisms of specific bacterial virulence factors can significantly contribute to antibacterial drug discovery. Helicobacter pylori is a Gram-negative microaerophilic bacterium that infects almost half of the world’s population, leading to gastric disorders and even gastric cancer. H. pylori expresses a series of virulence factors in the host, among which high-temperature requirement A (HpHtrA) is a newly identified serine protease secreted by H. pylori. HpHtrA cleaves the extracellular domain of the epithelial cell surface adhesion protein E-cadherin and disrupts gastric epithelial cell junctions, allowing H. pylori to access the intercellular space. Here we report the first crystal structure of HpHtrA at 3.0 Å resolution. The structure revealed a new type of HtrA protease trimer stabilized by unique N-terminal domain swapping distinct from other known HtrA homologs. We further observed that truncation of the N terminus completely abrogates HpHtrA trimer formation as well as protease activity. In the presence of unfolded substrate, HpHtrA assembled into cage-like 12-mers or 24-mers. Combining crystallographic, biochemical, and mutagenic data, we propose a mechanistic model of how HpHtrA recognizes and cleaves the well-folded E-cadherin substrate. Our study provides a fundamental basis for the development of anti-H. pylori agents by using a previously uncharacterized HtrA protease as a target.-
dc.languageeng-
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/-
dc.relation.ispartofJournal of Biological Chemistry-
dc.rightsJournal of Biological Chemistry. Copyright © American Society for Biochemistry and Molecular Biology, Inc.-
dc.rightsThis research was originally published in [Journal Name]. Author(s). Title. Journal Name. Year. Vol:pp-pp. © the American Society for Biochemistry and Molecular Biology-
dc.titleThe unique trimeric assembly of the virulence factor HtrA from Helicobacter pylori occurs via N-terminal domain swapping-
dc.typeArticle-
dc.identifier.emailLi, H: hylichem@hku.hk-
dc.identifier.emailSun, H: hsun@hku.hk-
dc.identifier.authoritySun, H=rp00777-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1074/jbc.RA119.007387-
dc.identifier.scopuseid_2-s2.0-85066144251-
dc.identifier.hkuros297868-
dc.identifier.volume294-
dc.identifier.spage7990-
dc.identifier.epage8000-
dc.identifier.isiWOS:000470656500003-
dc.publisher.placeUnited States-
dc.identifier.issnl0021-9258-

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