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Article

Structural Insights into the Active Site Formation of DUSP22 in N-loop-containing Protein Tyrosine Phosphatases

1
Institute of Bioinformatics and Structural Biology, Department of Life Science, National Tsing Hua University, Hsinchu 30013, Taiwan
2
Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7515; https://doi.org/10.3390/ijms21207515
Received: 28 August 2020 / Revised: 7 October 2020 / Accepted: 9 October 2020 / Published: 12 October 2020
(This article belongs to the Special Issue Structural Biology of Proteins and Peptides)
Cysteine-based protein tyrosine phosphatases (Cys-based PTPs) perform dephosphorylation to regulate signaling pathways in cellular responses. The hydrogen bonding network in their active site plays an important conformational role and supports the phosphatase activity. Nearly half of dual-specificity phosphatases (DUSPs) use three conserved residues, including aspartate in the D-loop, serine in the P-loop, and asparagine in the N-loop, to form the hydrogen bonding network, the D-, P-, N-triloop interaction (DPN–triloop interaction). In this study, DUSP22 is used to investigate the importance of the DPN–triloop interaction in active site formation. Alanine mutations and somatic mutations of the conserved residues, D57, S93, and N128 substantially decrease catalytic efficiency (kcat/KM) by more than 102-fold. Structural studies by NMR and crystallography reveal that each residue can perturb the three loops and induce conformational changes, indicating that the hydrogen bonding network aligns the residues in the correct positions for substrate interaction and catalysis. Studying the DPN–triloop interaction reveals the mechanism maintaining phosphatase activity in N-loop-containing PTPs and provides a foundation for further investigation of active site formation in different members of this protein class. View Full-Text
Keywords: hydrogen bonding network; active site; N-loop; DUSP22; DUSPs; Cys-based PTPs hydrogen bonding network; active site; N-loop; DUSP22; DUSPs; Cys-based PTPs
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MDPI and ACS Style

Lai, C.-H.; Chang, C.-C.; Chuang, H.-C.; Tan, T.-H.; Lyu, P.-C. Structural Insights into the Active Site Formation of DUSP22 in N-loop-containing Protein Tyrosine Phosphatases. Int. J. Mol. Sci. 2020, 21, 7515. https://doi.org/10.3390/ijms21207515

AMA Style

Lai C-H, Chang C-C, Chuang H-C, Tan T-H, Lyu P-C. Structural Insights into the Active Site Formation of DUSP22 in N-loop-containing Protein Tyrosine Phosphatases. International Journal of Molecular Sciences. 2020; 21(20):7515. https://doi.org/10.3390/ijms21207515

Chicago/Turabian Style

Lai, Chih-Hsuan, Co-Chih Chang, Huai-Chia Chuang, Tse-Hua Tan, and Ping-Chiang Lyu. 2020. "Structural Insights into the Active Site Formation of DUSP22 in N-loop-containing Protein Tyrosine Phosphatases" International Journal of Molecular Sciences 21, no. 20: 7515. https://doi.org/10.3390/ijms21207515

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