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

Journal Article · Wed Feb 01 00:00:00 EST 2017 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2017.01.014· OSTI ID:1421575

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

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.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: 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)
• Grant/Contract Number: AC02-06CH11357; 1-14-ACN-31; R01GM098482; ACB-12002; AGM-12006
• OSTI ID: 1421575
• Alternate ID(s): OSTI ID: 1368228; OSTI ID: 1413164
• Journal Information: Molecular Cell, Journal Name: Molecular Cell Vol. 65 Journal Issue: 4; ISSN 1097-2765
• Publisher: Elsevier
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
protein tyrosine phosphatase
PTP1B
enzyme
NMR spectroscopy
X-ray crystallography
allostery
protein dynamics
fast and intermediate timescale dynamics