Abstract

Article info 2015 3 (2)    003  (02)   pp.  111 ~ 116
Title Structural analysis of activity-modulating mutations of DUSP19
Authors Tae Jin Jeon, Kyoung Tae Nam and Seong Eon Ryu*
Institutions Department of Bioengineering, College of Engineering, College of Medicine, Hanyang University, 222 Wangsimri-rho, Seongdong-gu, Seoul 133-792, Korea. *Correspondence: ryuse@hanyang.ac.kr
Abstract The activity of cellular signaling proteins modulates cellular processes such as cell growth, immune responses, and neuronal development. Dual specificity phosphatases (DUSPs), which constitute a subfamily of protein tyrosine phosphatases (PTPs), are potential targets for therapeutic development. Recently, allosteric inhibitors of PTPs have shown promising results with regard to their potency, selectivity and membrane permeability. However, detailed understanding of the activity regulation of PTPs is limited. Thus, we determined crystal structures of activity-modulating mutants of DUSP19 for which strongly-diffracting crystals are available. One allosteric residue (Ile 187) and two active site residues (Ser 150 and Arg 156) were mutated to alanine. High-resolution crystal structure determination and enzyme kinetics analysis of the three mutants revealed that the mutations resulted in rearrangements in allosteric and local structures. In particular, cavityfilling rearrangements in the I187A mutant were conveyed to the active site, leading to allosteric regulation of enzyme activity.