Solution Structure of the MAPK Phosphatase PAC-1 Catalytic Domain: Insights into Substrate-Induced Enzymatic Activation of MKP

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-...

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Bibliographic Details
Published in:Structure (London) 2003-02, Vol.11 (2), p.155-164
Main Authors: Farooq, Amjad, Plotnikova, Olga, Chaturvedi, Gaurav, Yan, Sherry, Zeng, Lei, Zhang, Qiang, Zhou, Ming-Ming
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Catalytic Domain
Dual Specificity Phosphatase 2
enzymatic activation
Humans
Magnetic Resonance Spectroscopy
MAPK dephosphorylation
MKP phosphatase domain
Molecular Sequence Data
NMR structure
PAC-1
Protein Phosphatase 2
Protein Tyrosine Phosphatases - chemistry
Sequence Alignment
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Summary: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.
ISSN:0969-2126
1878-4186
DOI:10.1016/S0969-2126(02)00943-7