Cytotoxin-associated gene A (CagA) is generally accepted to be the most important virulence factor of Helicobacter pylori and increases the risk of developing gastric cancer. East Asian CagA, which includes the EPIYA-D segment at the C-terminal region, has a significantly higher gastric carcinogenic rate than Western CagA including the EPIYA-C segment. Although the amino acid polymorphism surrounding the EPIYA motif in the C-terminal region has been examined in detail, limited information is currently available on the amino acid polymorphism of the N-terminal region of East Asian CagA. In the present study, we analyzed the sequencing data of East Asian CagA that we obtained previously to detect amino acid changes (AACs) in the N-terminal region of East Asian CagA. Four highly frequent AACs in the N-terminal region of East Asian CagA were detected in our datasets, two of which (V356A, Y677F) exhibited reproducible specificity using a validation dataset from the NCBI database, which are candidate AACs related to the pathogenic function of CagA. We examined whether these AACs affect the functions of CagA in silico model. The computational docking simulation model showed that binding affinity between CagA and phosphatidylserine remained unchanged in the model of mutant CagA reflecting both AAC, whereas that between CagA and α5β1 integrin significantly increased. Based on whole genome sequencing data we herein identified novel specific AACs in the N-terminal regions of EPIYA-D that have the potential to change the function of CagA.
Keywords: Amino Acid Polymorphisms; East Asian CagA; Helicobacter pylori; In Silico; N-terminal Region.