Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA.

Schmidt, Thomas P; Perna, Anna M; Fugmann, Tim; Böhm, Manja; Hiss, Jan; Haller, Sarah; Götz, Camilla; Tegtmeyer, Nicole; Hoy, Benjamin; Rau, Tilman; Neri, Dario; Backert, Steffen; Schneider, Gisbert; Wessler, Silja (2016). Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA. Scientific Reports, 6(23264), p. 23264. Nature Publishing Group 10.1038/srep23264

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The cell adhesion protein and tumour suppressor E-cadherin exhibits important functions in the prevention of gastric cancer. As a class-I carcinogen, Helicobacter pylori (H. pylori) has developed a unique strategy to interfere with E-cadherin functions. In previous studies, we have demonstrated that H. pylori secretes the protease high temperature requirement A (HtrA) which cleaves off the E-cadherin ectodomain (NTF) on epithelial cells. This opens cell-to-cell junctions, allowing bacterial transmigration across the polarised epithelium. Here, we investigated the molecular mechanism of the HtrA-E-cadherin interaction and identified E-cadherin cleavage sites for HtrA. Mass-spectrometry-based proteomics and Edman degradation revealed three signature motifs containing the [VITA]-[VITA]-x-x-D-[DN] sequence pattern, which were preferentially cleaved by HtrA. Based on these sites, we developed a substrate-derived peptide inhibitor that selectively bound and inhibited HtrA, thereby blocking transmigration of H. pylori. The discovery of HtrA-targeted signature sites might further explain why we detected a stable 90 kDa NTF fragment during H. pylori infection, but also additional E-cadherin fragments ranging from 105 kDa to 48 kDa in in vitro cleavage experiments. In conclusion, HtrA targets E-cadherin signature sites that are accessible in in vitro reactions, but might be partially masked on epithelial cells through functional homophilic E-cadherin interactions.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology

UniBE Contributor:

Rau, Tilman

ISSN:

2045-2322

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Doris Haefelin

Date Deposited:

22 Dec 2016 16:06

Last Modified:

15 Jan 2017 02:14

Publisher DOI:

10.1038/srep23264

PubMed ID:

26983597

BORIS DOI:

10.7892/boris.92059

URI:

https://boris.unibe.ch/id/eprint/92059

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