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Volume 10, Issue 8 (Suppl) J Proteomics Bioinform, an open access journal
ISSN: 0974-276X Structural Biology 2017
September 18-20, 2017
9th International Conference on
Structural Biology
September 18-20, 2017 Zurich, Switzerland
Molecular mechanism of SHP2 activation by CagA from Helicobacter pylori
Miki Senda 1, Takeru Hayashi2, Nobuhiro Suzuki 1, Lisa Nagase 1, Masanori Hatakeyama2 and Toshiya Senda1
1High Energy Accelerator Research Organization, Japan
2The University of Tokyo, Japan
Helicobacter pylori which is known as a major risk factor of stomach cancer, delivers an effector protein CagA into gastric
epithelial cells. CagA then promiscuously interact with host proteins, SHP2 and PAR1b, to deregulate these proteins,
potentiating oncogenic signaling. CagA comprises an N-terminal structured region and a C-terminal intrinsically disordered
region which interacts with the host proteins. We already determined the crystal structure of the N-terminal region of CagA
(1–3). The crystal structure revealed that the basic amino-acid cluster in the N-terminal region is utilized to localized CagA at
the inner face of the plasma membrane. After localization, short segments including Glu-Pro-Ile-Tyr-Ala (EPIYA) motif in the
C-terminal disordered region are phosphorylated by Src and interact with SHP2 to deregulate its phosphatase activity. In this
study, we have analyzed the structure-function relationship of the EPIYA-segments of CagA. Based on the sequence flanking
each of the EPIYA motifs, four types of EPIYA segments, A, B, C, and D, have been identified (4). It is already known that
combinations of the EPIYA segments are geographically different (Western and East Asian CagA) and affect CagA’s oncogenic
activity. While Western CagA with EPIYA-A, B, and C segments has weak oncogenic activity, Western CagA with EPIYA-A, B
and multiple EPIYA-C segments shows increased oncogenic activity (5). East Asian CagA, which has much higher oncogenic
activity than Western ones, typically possesses EPIYA-A, B, and D in the C-terminal region. Our biochemical data revealed
that oncogenic activity of CagA is correlated with binding affinity for SH2 domain of SHP2 (SH2_SHP2). We have analyzed
the interaction between SH2_SHP2 and the EPIYA-C/D segment using biochemical, crystallographic, and physicochemical
methods and revealed two types of activation mechanisms of SHP2. In our presentation, we will report that East Asian and
Western CagA utilize two distinct activation mechanisms of SHP2.
Biography
Miki Senda has completed her PhD at 2008 from Nagaoka University of Technology. She is an Assistant Professor of Structural Biology Research Center in High
Energy Accelerator Research Organization (KEK). She has several collaborations, in which she has worked as an expert of protein crystallization and crystal quality
improvement. She received Oxford Cryosystems Low Temperature Prize at the 63rd Annual Meeting of the American Crystallographic Association (ACA) in 2013.
Miki Senda et al., J Proteomics Bioinform 2017, 10:8(Suppl)
DOI: 10.4172/0974-276X-C1-0100