Structural-dynamic insights into the H. pylori cytotoxin-associated gene A (CagA) and its abrogation to interact with the tumor suppressor protein ASPP2 using decoy peptides

Muhammad Junaid, Masaud Shah, Abbas Khan, Cheng Dong Li, Muhammad Tahir Khan, Aman Chandra Kaushik, Arif Ali, Aamir Mehmood, Asma Sindhoo Nangraj, Sangdun Choi, Dong Qing Wei

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Helicobacter pylori (H. pylori) is one of the most extensively studied Gram-negative bacteria due to its implication in gastric cancer. The oncogenicity of H. pylori is associated with cytotoxin-associated gene A (CagA), which is injected into epithelial cells lining the stomach. Both the C- and N-termini of CagA are involved in the interaction with several host proteins, thereby disrupting vital cellular functions, such as cell adhesion, cell cycle, intracellular signal transduction, and cytoskeletal structure. The N-terminus of CagA interacts with the tumor-suppressing protein, apoptosis-stimulating protein of p53 (ASPP2), subsequently disrupting the apoptotic function of tumor suppressor gene p53. Here, we present the in-depth molecular dynamic mechanism of the CagA–ASPP2 interaction and highlight hot-spot residues through in silico mutagenesis. Our findings are in agreement with previous studies and further suggest other residues that are crucial for the CagA–ASPP2 interaction. Furthermore, the ASPP2-binding pocket possesses potential druggability and could be engaged by decoy peptides, identified through a machine-learning system and suggested in this study. The binding affinities of these peptides with CagA were monitored through extensive computational procedures and reported herein. While CagA is crucial for the oncogenicity of H. pylori, our designed peptides possess the potential to inhibit CagA and restore the tumor suppressor function of ASPP2.

Original languageEnglish
Pages (from-to)4035-4050
Number of pages16
JournalJournal of Biomolecular Structure and Dynamics
Volume37
Issue number15
DOIs
StatePublished - 13 Oct 2019
Externally publishedYes

Keywords

  • ASPP2
  • Apoptosis
  • CagA
  • MD simulation
  • peptide inhibitors

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Fingerprint

Dive into the research topics of 'Structural-dynamic insights into the H. pylori cytotoxin-associated gene A (CagA) and its abrogation to interact with the tumor suppressor protein ASPP2 using decoy peptides'. Together they form a unique fingerprint.

Cite this