Structural Basis and Functional Consequence of Helicobacter pylori CagA Multimerization in Cells

Abstract

, thereby inducing an elongated cell shape known as the hummingbird phenotype. In this study, we found that CagA multimerizes in cells in a manner independent of its tyrosine phosphorylation. Using a series of CagA mutants, we identified a conserved amino acid sequence motif (FPLXRXXXVXDL-SKVG), which mediates CagA multimerization, within the EPIYA-C segment as well as in a sequence that located immediately downstream of the EPIYA-C or EPIYA-D segment. We also found that a phosphorylation-resistant CagA, which multimerizes but cannot bind SHP-2, inhibits the wild-type CagA-SHP-2 complex formation and abolishes induction of the hummingbird phenotype. Thus, SHP-2 binds to a preformed and tyrosinephosphorylated CagA multimer via its two Src homology 2 domains. These results, in turn, indicate that CagA multimerization is a prerequisite for CagA-SHP-2 interaction and subsequent deregulation of SHP-2. The present work raises the possibility that inhibition of CagA multimerization abolishes pathophysiological activities of CagA that promote gastric carcinogenesis.

Structural insights into Helicobacter pylori oncoprotein CagA interaction with β1 integrin

“…S4A). CagA was found to form multimers via the MKI sequences (also called CagA multimerization sequence-CM) and this multimerization increase CagA activity on the SHP2 phosphatase (20,21). Because the MKI (CM) sequences are not present in the CagA 1-884 fragment, the oligomeric state of CagA 1-884 was investigated.…”

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…Conversely, PAR1 binds to the C-terminal 16-aminoacid sequence of CagA known as the CagA-multimerization sequence (Ren et al, 2006) (Figure 1). As PAR1 is present as a dimer (Panneerselvam et al, 2006), two CagA proteins passively dimerize upon interacting with a PAR1 dimer and, following tyrosine phosphorylation by Src, the PAR1-mediated CagA dimer forms a stable complex with a single SHP-2 molecule through the two SH2 domains of SHP-2 (Figure 2b).…”

Variations in the multimerization region of the Helicobacter pylori cytotoxin CagA affect virulence

“…This is a 16-amino acid sequence, which is responsible for dimerization of CagA (9). Similar to the EPIYA patterns, Western and Eastern CM sequences have been identified (10).…”

“…Within the variable region of the cagA gene is another motif called the CagA multimerization (CM) region (9). This is a 16-amino acid sequence, which is responsible for dimerization of CagA (9).…”