Journal
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 37, Issue 15, Pages 4035-4050Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2018.1537895
Keywords
Apoptosis; ASPP2; CagA; MD simulation; peptide inhibitors
Categories
Funding
- Ministry of Science and Technology of China [2016YFA0501703]
- Ph.D. Programs Foundation of Ministry of Education of China [20120073110057]
- State Key Lab on Microbial Metabolism
- Joint Research Funds for Medical and Engineering & Scientific Research at Shanghai Jiao Tong University
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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.
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