Structural Biology

Biography

Biography: Tzu-Ching Meng

Abstract

The Ras signaling cascade acts as a key driver in human colon cancer progression. Among the modules in this pathway, p38gamma (MAPK12) and its specific protein tyrosine phosphatase PTPN3 (PTPH1) are critical regulators responsible for Ras oncogenic activity. However, the molecular basis for their interaction is completely unknown. Here we report the unique architecture of the PTPN3-p38gamma complex by employing an advanced hybrid method integrating X-ray crystallography, small-angle X-ray scattering (SAXS) and chemical cross-linking/mass spectrometry (CX-MS). Our crystal structure of PTPN3 in complex with the p38gamma phosphopeptide presented a unique feature of the E-loop that defines the substrate specificity of PTPN3 towards fully activated p38gamma. The low-resolution structure demonstrated the formation of an active-state or a resting-state complex of PTPN3-p38gamma. We showed a regulatory function of PTPN3’s PDZ domain, which stabilizes the active-state complex through interaction with the PDZ-binding motif of p38gamma. Using SAXS and CX-MS approaches, we found that binding of the PDZ domain to the PDZ-binding motif lifts the atypical auto-inhibitory constraint of PTPN3, enabling efficient tyrosine dephosphorylation of p38gamma to occur. Our findings emphasize the potential of structural approach for PTPN3-p38gamma complex that may deliver new therapeutic strategies against Ras-mediated oncogenesis in colon cancer.

References:

1. Pan KT, Chen YY, Pu TH, Chao YS, Yang CY, Bomgarden RD, Rogers JC, Meng, TC*, Khoo, KH* (2014) Mass spectrometry based quantitative proteomics for dissecting multiplexed redox cysteine modifications in nitric oxide-protected cardiomyocyte under hypoxia. Antioxidant and Redox Signaling, 20:1365-1381.
2. Santhanam A, Peng WH, Yu YT, Sang TK, Chen GC*, Meng TC* (2014) Ecdysone-induced receptor tyrosine phosphatase PTP52F regulates Drosophila midgut histolysis by enhancement of autophagy and apoptosis. Mol. Cell. Biol., 34:1594-1606.
3. Chen KE, Lin SY, Wu M J,  Ho MR, Santhanam A, Chou CC, Meng TC*, Wang AHJ* (2014) Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain modulated complex formation. Science Signaling, 7: ra98 p1-12.
4. Chen KE, Li MY, Chou CC, Ho MR, Chen GC, Meng TC*, Wang AHJ* (2015) Substrate specificity and plasticity of FERM-containing protein tyrosine phosphatases. Structure, 23: 653–664.
5. Hsu MF, Pan KT, Chang FY, Khoo KH, Urlaub H, Chang GD*, Haj FG*, and Meng TC* (2016) S-Nitrosylation of endogenous protein tyrosine phosphatases in endothelial insulin signaling. Free Rad Biol Med, 99: 199-213.