Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/ijms231911299
Keywords
NMR; INPPL1; SH2 domain; tyrosine phosphorylation; protein-protein interaction
Funding
- National Key R&D Program of China [2018YFA0704000]
- National Natural Science Foundation of China [22074152, 21921004, 21991080, 21735007]
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This study investigated the interaction between SHIP2-SH2 and CagA protein from a structural perspective using NMR spectroscopy. The results showed that EPIYA-C and -D have high affinity to the binding site of SHIP2-SH2, while EPIYA-A and -B have weak affinity. The study also revealed the selective preference of SHIP2-SH2 for aliphatic residues at the pY+3 position in its ligand. These findings provide insights into the ligand sequence and the mechanism by which CagA protein hijacks SHIP2.
SHIP2 is a multi-domain inositol 5-phosphatase binding to a variety of phosphotyrosine (pY)-containing proteins through its SH2 domain, so as to regulate various cell signaling pathways by modulating the phosphatidylinositol level in the plasma membrane. Unfavorably, Helicobacter pylori can hijack SHIP2 through the CagA protein to induce gastric cell carcinogenesis. To date, the interaction between SHIP2 and CagA was not analyzed from a structural point of view. Here, the binding of SHIP2-SH2 with Tyr-phosphorylated peptides from four EPIYA motifs (A/B/C/D) in CagA was studied using NMR spectroscopy. The results showed that EPIYA-C and -D bind to a similar interface of SHIP2-SH2, including a pY-binding pocket and a hydrophobic pocket, to achieve high affinity, while EPIYA-A and -B bind to a smaller interface of SHIP2-SH2 with weak affinity. By summarizing the interface and affinity of SHIP2-SH2 for CagA EPIYA-A/B/C/D, c-MET and FcgR2B ITIM, it was proposed that, potentially, SHIP2-SH2 has a selective preference for L > I > V for the aliphatic residues at the pY+3 position in its ligand. This study reveals the rule of the ligand sequence bound by SHIP2-SH2 and the mechanism by which CagA protein hijacks SHIP2, which will help design a peptide inhibitor against SHIP2-SH2.
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