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Title: Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery

Abstract

Protein function originates from a cooperation of structural rigidity, dynamics at different timescales, and allostery. However, how these three pillars of protein function are integrated is still only poorly understood. Here we show how these pillars are connected in Protein Tyrosine Phosphatase 1B (PTP1B), a drug target for diabetes and cancer that catalyzes the dephosphorylation of numerous substrates in essential signaling pathways. By combining new experimental and computational data on WT-PTP1B and ≥10 PTP1B variants in multiple states, we discovered a fundamental and evolutionarily conserved CH/π switch that is critical for positioning the catalytically important WPD loop. Furthermore, our data show that PTP1B uses conformational and dynamic allostery to regulate its activity. This shows that both conformational rigidity and dynamics are essential for controlling protein activity. We surmise this connection between rigidity and dynamics at different timescales is likely a hallmark of all enzyme function.

Authors:
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Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC); American Diabetes Association (ADA); Lundbeck Foundation; Novo Nordisk Foundation; National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS)
OSTI Identifier:
1421575
Alternate Identifier(s):
OSTI ID: 1368228; OSTI ID: 1413164
Grant/Contract Number:  
AC02-06CH11357; 1-14-ACN-31; R01GM098482; ACB-12002; AGM-12006
Resource Type:
Journal Article: Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Name: Molecular Cell Journal Volume: 65 Journal Issue: 4; Journal ID: ISSN 1097-2765
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; protein tyrosine phosphatase; PTP1B; enzyme; NMR spectroscopy; X-ray crystallography; allostery; protein dynamics; fast and intermediate timescale dynamics

Citation Formats

Choy, Meng S., Li, Yang, Machado, Luciana E. S. F., Kunze, Micha B. A., Connors, Christopher R., Wei, Xingyu, Lindorff-Larsen, Kresten, Page, Rebecca, and Peti, Wolfgang. Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery. United States: N. p., 2017. Web. doi:10.1016/j.molcel.2017.01.014.
Choy, Meng S., Li, Yang, Machado, Luciana E. S. F., Kunze, Micha B. A., Connors, Christopher R., Wei, Xingyu, Lindorff-Larsen, Kresten, Page, Rebecca, & Peti, Wolfgang. Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery. United States. https://doi.org/10.1016/j.molcel.2017.01.014
Choy, Meng S., Li, Yang, Machado, Luciana E. S. F., Kunze, Micha B. A., Connors, Christopher R., Wei, Xingyu, Lindorff-Larsen, Kresten, Page, Rebecca, and Peti, Wolfgang. 2017. "Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery". United States. https://doi.org/10.1016/j.molcel.2017.01.014.
@article{osti_1421575,
title = {Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery},
author = {Choy, Meng S. and Li, Yang and Machado, Luciana E. S. F. and Kunze, Micha B. A. and Connors, Christopher R. and Wei, Xingyu and Lindorff-Larsen, Kresten and Page, Rebecca and Peti, Wolfgang},
abstractNote = {Protein function originates from a cooperation of structural rigidity, dynamics at different timescales, and allostery. However, how these three pillars of protein function are integrated is still only poorly understood. Here we show how these pillars are connected in Protein Tyrosine Phosphatase 1B (PTP1B), a drug target for diabetes and cancer that catalyzes the dephosphorylation of numerous substrates in essential signaling pathways. By combining new experimental and computational data on WT-PTP1B and ≥10 PTP1B variants in multiple states, we discovered a fundamental and evolutionarily conserved CH/π switch that is critical for positioning the catalytically important WPD loop. Furthermore, our data show that PTP1B uses conformational and dynamic allostery to regulate its activity. This shows that both conformational rigidity and dynamics are essential for controlling protein activity. We surmise this connection between rigidity and dynamics at different timescales is likely a hallmark of all enzyme function.},
doi = {10.1016/j.molcel.2017.01.014},
url = {https://www.osti.gov/biblio/1421575}, journal = {Molecular Cell},
issn = {1097-2765},
number = 4,
volume = 65,
place = {United States},
year = {Wed Feb 01 00:00:00 EST 2017},
month = {Wed Feb 01 00:00:00 EST 2017}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at https://doi.org/10.1016/j.molcel.2017.01.014

Citation Metrics:
Cited by: 62 works
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Works referencing / citing this record:

Exploring the allosteric mechanism of protein tyrosine phosphatase 1B by molecular dynamics simulations
journal, October 2019


Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
journal, October 2018


Minimally disruptive optical control of protein tyrosine phosphatase 1B
journal, February 2020


Dynamic activation and regulation of the mitogen-activated protein kinase p38
journal, April 2018


Computational Insight into Protein Tyrosine Phosphatase 1B Inhibition: A Case Study of the Combined Ligand- and Structure-Based Approach
journal, January 2017