title: Solution structure of the MAPK phosphatase PAC-1 catalytic domain. Insights into substrate-induced enzymatic activation of MKP.
abstract: Inactivation of mitogen-activated protein kinases (MAPKs) by MAPK phosphatases (MKPs) is accomplished via substrate-induced activation of the latter enzymes; however, the structural basis for the underlying mechanism remains elusive. Here, we report the three-dimensional solution structure of the C-terminal phosphatase domain of the prototypical MKP PAC-1, determined when bound to phosphate. Structural and biochemical analyses reveal unique active site geometry of the enzyme important for binding to phosphorylated threonine and tyrosine of MAPK ERK2. Our study further demonstrates that the dynamic interaction between the N-terminal kinase binding domain and the C-terminal phosphatase domain of an MKP is directly coupled to MAPK-induced conformational change of the phosphatase active site, which is essential for eliciting its full enzymatic activity.
authors.affiliation: Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Amjad
authors.initials: A
authors.lastname: Farooq
authors.forename: Olga
authors.initials: O
authors.lastname: Plotnikova
authors.forename: Gaurav
authors.initials: G
authors.lastname: Chaturvedi
authors.forename: Sherry
authors.initials: S
authors.lastname: Yan
authors.forename: Lei
authors.initials: L
authors.lastname: Zeng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D054641:Dual Specificity Phosphatase 2; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D016415:Sequence Alignment
chemical_list: D054648:Protein Phosphatase 2; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2; D017027:Protein Tyrosine Phosphatases