4qum

Publication Abstract from PubMed

The mitogen-activated protein kinase p38gamma (also known as MAPK12) and its specific phosphatase PTPN3 (also known as PTPH1) cooperate to promote Ras-induced oncogenesis. We determined the architecture of the PTPN3-p38gamma complex by a hybrid method combining x-ray crystallography, small-angle x-ray scattering, and chemical cross-linking coupled to mass spectrometry. A unique feature of the glutamic acid-containing loop (E-loop) of the phosphatase domain defined the substrate specificity of PTPN3 toward fully activated p38gamma. The solution structure revealed the formation of an active-state complex between p38gamma and the phosphatase domain of PTPN3. The PDZ domain of PTPN3 stabilized the active-state complex through an interaction with the PDZ-binding motif of p38gamma. This interaction alleviated autoinhibition of PTPN3, enabling efficient tyrosine dephosphorylation of p38gamma. Our findings may enable structure-based drug design targeting the PTPN3-p38gamma interaction as an anticancer therapeutic.

Reciprocal allosteric regulation of p38gamma and PTPN3 involves a PDZ domain-modulated complex formation.,Chen KE, Lin SY, Wu MJ, Ho MR, Santhanam A, Chou CC, Meng TC, Wang AH Sci Signal. 2014 Oct 14;7(347):ra98. doi: 10.1126/scisignal.2005722. PMID:25314968^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.