Insights into structure and function of SHIP2-SH2: homology modeling, docking, and molecular dynamics study

Abstract

SRC homology 2 (SH2)-containing inositol 5′-phosphatase protein (SHIP2) is a potential target for type 2 diabetes. Its ability to dephosphorylate the lipid messenger phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], important for insulin signaling, makes it an important target against type 2 diabetes. The insulin-induced SHIP2 interaction with Shc is very important for the membrane localization and functioning of SHIP2. There is a bidentate relationship between the two proteins where two domains each from SHIP2 and Shc are involved in mutual binding. However in the present study, the SHIP2-SH2 domain binding with the phosphorylated tyrosine 317 on the collagen-homology (CH) domain of Shc, has been studied due to the indispensability of this interaction in SHIP2 localization. In the absence of the crystal structure of SHIP2-SH2, its structural model was developed followed by tracking its molecular interactions with Shc through molecular docking and dynamics studies. This study revealed much about the structural interactions between the SHIP2-SH2 and Shc-CH. Finally, docking study of a nonpeptide inhibitor into the SHIP2-SH2 domain further confirmed the structural interactions involved in ligand binding and also proposed the inhibitor as a major starting point against SHIP2-SH2 inhibition. The insights gained from the current study should prove useful in the design of more potent inhibitors against type 2 diabetes.

SHIP2 inhibition alters redox‐induced PI3K/AKT and MAP kinase pathways via PTEN over‐activation in cervical cancer cells

“…As a negative regulator of PI(3,4,5)P3 level, SHIP2 inhibition in liver cancer cells enhances PI3K/AKT signaling and prevents ROS production after palmitate treatment [29], whereas its overexpression suppresses PI3K/AKT signaling and cell growth in gastric cancer cells [27]. SHIP2 and PTEN are the major negative regulators of PI3K/AKT signaling [18–20], and both proteins are highly expressed in cervical cancer cell lines HeLa and SiHa (Fig. 1A and Fig.…”

“…PTEN dephosphorylates the three-position phosphate of PI (3,4,5)P3 and Phosphatidylinositol (3,4)-bisphosphate (PI(3,4)P2) to generate, respectively, PI(4,5)P2 and PI4P, and this event results in suppression of AKT signaling [18]. SHIP2 dephosphorylates the five-position phosphate from PI (3,4,5)P3 to generate PI(3,4)P2, leading also to inhibition of AKT-mediated signaling pathways in response to growth factor like insulin [19,20]. Previous studies have shown that SHIP2 plays a role in regulation of PI3K-dependent insulin signaling [21][22][23].…”

Solution structure of SHIP2 SH2 domain and its interaction with a phosphotyrosine peptide from c-MET

“…The structures of the 5-phosphatase domain and the SAM domain of SHIP2 have been well studied [27–30]. However, although a 3D model of SHIP2 SH2 domain was described previously [31], the experimental structure had not yet been reported. In this study, we determined the solution structure of SHIP2-SH2 domain using NMR spectroscopy.…”

Design of Cinnamic Acid Derivatives and Molecular Docking Toward Human-Neutral a-Glucosidase by using Homology Modeling

“…Ligand-based virtual screening approach was used in here to calculate the lowest binding energy between α-glucosidase enzyme with ligand and also to study their binding affinity 16 . We chose the enzyme α-glucosidase C-neutral protein in humans as the target for virtual screening [17][18][19][20][21][22][23][24] .…”