Conserved conformational dynamics determine enzyme activity

Torgeson, Kristiane R.; Clarkson, Michael W.; Granata, Daniele; Lindorff-Larsen, Kresten; Page, Rebecca; Peti, Wolfgang

doi:10.1126/sciadv.abo5546

Title: Conserved conformational dynamics determine enzyme activity

Journal Article · Wed Aug 03 00:00:00 EDT 2022 · Science Advances

DOI:https://doi.org/10.1126/sciadv.abo5546· OSTI ID:1903983

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^[2]; Granata, Daniele ^[3];

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Univ. of Arizona, Tucson, AZ (United States); University of Connecticut Health, Farmington, CT (United States)
Univ. of Arizona, Tucson, AZ (United States)
Univ. of Copenhagen (Denmark)
University of Connecticut Health, Farmington, CT (United States)

Homologous enzymes often exhibit different catalytic rates despite a fully conserved active site. The canonical view is that an enzyme sequence defines its structure and function and, more recently, that intrinsic protein dynamics at different time scales enable and/or promote catalytic activity. Here, we show that, using the protein tyrosine phosphatase PTP1B, residues surrounding the PTP1B active site promote dynamically coordinated chemistry necessary for PTP1B function. However, residues distant to the active site also undergo distinct intermediate time scale dynamics and these dynamics are correlated with its catalytic activity and thus allow for different catalytic rates in this enzyme family. We identify these previously undetected motions using coevolutionary coupling analysis and nuclear magnetic resonance spectroscopy. Our findings strongly indicate that conserved dynamics drives the enzymatic activity of the PTP family. Characterization of these conserved dynamics allows for the identification of novel regulatory elements (therapeutic binding pockets) that can be leveraged for the control of enzymes.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); American Diabetes Association; National Institute of General Medicine Science (NIGMS); USDOE Office of Science (SC), Biological and Environmental Research (BER); Novo Nordisk Foundation

Grant/Contract Number:: AC02-76SF00515; 1-14-ACN-31; R01GM098482; P41GM103393

OSTI ID:: 1903983

Journal Information:: Science Advances, Vol. 8, Issue 31; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

References (50)

Conservation of Dynamics Associated with Biological Function in an Enzyme Superfamily Narayanan, Chitra; Bernard, David N.; Bafna, Khushboo Structure, Vol. 26, Issue 3 https://doi.org/10.1016/j.str.2018.01.015	journal	March 2018
Protein Tyrosine Phosphatases in the Human Genome Alonso, Andres; Sasin, Joanna; Bottini, Nunzio Cell, Vol. 117, Issue 6 https://doi.org/10.1016/j.cell.2004.05.018	journal	June 2004
Quantitative measurement of exchange dynamics in proteins via 13C relaxation dispersion of 13CHD2-labeled samples Rennella, Enrico; Schuetz, Anne K.; Kay, Lewis E. Journal of Biomolecular NMR, Vol. 65, Issue 2 https://doi.org/10.1007/s10858-016-0038-9	journal	June 2016
Ligand-dependent Dynamics and Intramolecular Signaling in a PDZ Domain Fuentes, Ernesto J.; Der, Channing J.; Lee, Andrew L. Journal of Molecular Biology, Vol. 335, Issue 4 https://doi.org/10.1016/j.jmb.2003.11.010	journal	January 2004
Enzymes at work are enzymes in motion Saleh, Tamjeed; Kalodimos, Charalampos G. Science, Vol. 355, Issue 6322 https://doi.org/10.1126/science.aal4632	journal	January 2017
The Michaelis Complex of Arginine Kinase Samples the Transition State at a Frequency That Matches the Catalytic Rate Peng, Yu; Hansen, Alexandar L.; Bruschweiler-Li, Lei Journal of the American Chemical Society, Vol. 139, Issue 13 https://doi.org/10.1021/jacs.7b00236	journal	March 2017
Patterns of coevolving amino acids unveil structural and dynamical domains Granata, Daniele; Ponzoni, Luca; Micheletti, Cristian Proceedings of the National Academy of Sciences, Vol. 114, Issue 50 https://doi.org/10.1073/pnas.1712021114	journal	November 2017
Structural Basis for Inhibition of the Protein Tyrosine Phosphatase 1B by Phosphotyrosine Peptide Mimetics ^, Groves, Matthew R.; Yao, Zhu-Jun; Roller, Peter P. Biochemistry, Vol. 37, Issue 51 https://doi.org/10.1021/bi9816958	journal	December 1998
Conservation of Side-Chain Dynamics Within a Protein Family Law, Anthony B.; Fuentes, Ernesto J.; Lee, Andrew L. Journal of the American Chemical Society, Vol. 131, Issue 18 https://doi.org/10.1021/ja809915a	journal	April 2009
Structural and Evolutionary Relationships among Protein Tyrosine Phosphatase Domains Andersen, J. N.; Mortensen, O. H.; Peters, G. H. Molecular and Cellular Biology, Vol. 21, Issue 21 https://doi.org/10.1128/MCB.21.21.7117-7136.2001	journal	November 2001
Structure-based Design of a Low Molecular Weight, Nonphosphorus, Nonpeptide, and Highly Selective Inhibitor of Protein-tyrosine Phosphatase 1B Iversen, Lars Fogh; Andersen, Henrik Sune; Branner, Sven Journal of Biological Chemistry, Vol. 275, Issue 14 https://doi.org/10.1074/jbc.275.14.10300	journal	April 2000
The challenge of predicting distal active site mutations in computational enzyme design Osuna, Sílvia WIREs Computational Molecular Science, Vol. 11, Issue 3 https://doi.org/10.1002/wcms.1502	journal	August 2020
Defining the Structural Basis for Allosteric Product Release from E. coli Dihydrofolate Reductase Using NMR Relaxation Dispersion Oyen, David; Fenwick, R. Bryn; Aoto, Phillip C. Journal of the American Chemical Society, Vol. 139, Issue 32 https://doi.org/10.1021/jacs.7b05958	journal	July 2017
Improved contact prediction in proteins: Using pseudolikelihoods to infer Potts models Ekeberg, Magnus; Lövkvist, Cecilia; Lan, Yueheng Physical Review E, Vol. 87, Issue 1 https://doi.org/10.1103/PhysRevE.87.012707	journal	January 2013
Intrinsic dynamics of an enzyme underlies catalysis Eisenmesser, Elan Z.; Millet, Oscar; Labeikovsky, Wladimir Nature, Vol. 438, Issue 7064 https://doi.org/10.1038/nature04105	journal	November 2005
Choreographing an enzyme's dance Villali, Janice; Kern, Dorothee Current Opinion in Chemical Biology, Vol. 14, Issue 5 https://doi.org/10.1016/j.cbpa.2010.08.007	journal	October 2010
Molecular Basis for the Dephosphorylation of the Activation Segment of the Insulin Receptor by Protein Tyrosine Phosphatase 1B Salmeen, Annette; Andersen, Jannik N.; Myers, Michael P. Molecular Cell, Vol. 6, Issue 6 https://doi.org/10.1016/S1097-2765(00)00137-4	journal	December 2000
Cooperative dynamics across distinct structural elements regulate PTP1B activity Torgeson, Kristiane R.; Clarkson, Michael W.; Kumar, Ganesan Senthil Journal of Biological Chemistry, Vol. 295, Issue 40 https://doi.org/10.1074/jbc.RA120.014652	journal	October 2020
Uncovering the Molecular Interactions in the Catalytic Loop That Modulate the Conformational Dynamics in Protein Tyrosine Phosphatase 1B Cui, Danica S.; Lipchock, James Michael; Brookner, Dennis Journal of the American Chemical Society, Vol. 141, Issue 32 https://doi.org/10.1021/jacs.9b04470	journal	July 2019
UniRef clusters: a comprehensive and scalable alternative for improving sequence similarity searches Suzek, B. E.; Wang, Y.; Huang, H. Bioinformatics, Vol. 31, Issue 6 https://doi.org/10.1093/bioinformatics/btu739	journal	November 2014
A Dynamic Knockout Reveals That Conformational Fluctuations Influence the Chemical Step of Enzyme Catalysis Bhabha, G.; Lee, J.; Ekiert, D. C. Science, Vol. 332, Issue 6026 https://doi.org/10.1126/science.1198542	journal	April 2011
Crystal structure of human protein tyrosine phosphatase 1B Barford, D.; Flint, A.; Tonks, N. Science, Vol. 263, Issue 5152 https://doi.org/10.1126/science.8128219	journal	March 1994
Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases Crean, Rory M.; Biler, Michal; van der Kamp, Marc W. Journal of the American Chemical Society, Vol. 143, Issue 10 https://doi.org/10.1021/jacs.0c11806	journal	March 2021
Hinge-shift mechanism as a protein design principle for the evolution of β-lactamases from substrate promiscuity to specificity Modi, Tushar; Risso, Valeria A.; Martinez-Rodriguez, Sergio Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-22089-0	journal	March 2021
Conformational dynamics and enzyme evolution Petrović, Dušan; Risso, Valeria A.; Kamerlin, Shina Caroline Lynn Journal of The Royal Society Interface, Vol. 15, Issue 144 https://doi.org/10.1098/rsif.2018.0330	journal	July 2018
Principles that Govern the Folding of Protein Chains Anfinsen, C. B. Science, Vol. 181, Issue 4096 https://doi.org/10.1126/science.181.4096.223	journal	July 1973
Linkage between dynamics and catalysis in a thermophilic-mesophilic enzyme pair Wolf-Watz, Magnus; Thai, Vu; Henzler-Wildman, Katherine Nature Structural & Molecular Biology, Vol. 11, Issue 10 https://doi.org/10.1038/nsmb821	journal	August 2004
The Dynamic Energy Landscape of Dihydrofolate Reductase Catalysis Boehr, D. D.; McElheny, D.; Dyson, H. J. Science, Vol. 313, Issue 5793, p. 1638-1642 https://doi.org/10.1126/science.1130258	journal	September 2006
Purification of the major protein-tyrosine-phosphatases of human placenta. Tonks, N. K.; Diltz, C. D.; Fischer, E. H. Journal of Biological Chemistry, Vol. 263, Issue 14 https://doi.org/10.1016/S0021-9258(18)68702-2	journal	May 1988
Quantitative ¹³C and ²H NMR Relaxation Studies of the 723-Residue Enzyme Malate Synthase G Reveal a Dynamic Binding Interface Tugarinov, Vitali; Kay, Lewis E. Biochemistry, Vol. 44, Issue 49 https://doi.org/10.1021/bi0519809	journal	November 2005
NMR spectroscopy captures the essential role of dynamics in regulating biomolecular function Alderson, T. Reid; Kay, Lewis E. Cell, Vol. 184, Issue 3 https://doi.org/10.1016/j.cell.2020.12.034	journal	February 2021
NMR View: A computer program for the visualization and analysis of NMR data Johnson, Bruce A.; Blevins, Richard A. Journal of Biomolecular NMR, Vol. 4, Issue 5 https://doi.org/10.1007/BF00404272	journal	September 1994
Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery Choy, Meng S.; Li, Yang; Machado, Luciana E. S. F. Molecular Cell, Vol. 65, Issue 4 https://doi.org/10.1016/j.molcel.2017.01.014	journal	February 2017
Crystal Structure of TCPTP Unravels an Allosteric Regulatory Role of Helix α7 in Phosphatase Activity Singh, Jai Prakash; Lin, Meng-Jung; Hsu, Shu-Fang Biochemistry, Vol. 60, Issue 51 https://doi.org/10.1021/acs.biochem.1c00519	journal	December 2021
Visualization of the Cysteinyl-phosphate Intermediate of a Protein-tyrosine Phosphatase by X-ray Crystallography Pannifer, Andrew D. B.; Flint, Andrew J.; Tonks, Nicholas K. Journal of Biological Chemistry, Vol. 273, Issue 17 https://doi.org/10.1074/jbc.273.17.10454	journal	April 1998
The catalytic activity of TCPTP is auto-regulated by its intrinsically disordered tail and activated by Integrin alpha-1 Singh, Jai Prakash; Li, Yang; Chen, Yi-Yun Nature Communications, Vol. 13, Issue 1 https://doi.org/10.1038/s41467-021-27633-6	journal	January 2022
NMR detection of multiple transitions to low-populated states in azurin Korzhnev, D. M. Protein Science, Vol. 12, Issue 1 https://doi.org/10.1110/ps.0225403	journal	January 2003
Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling Zhang, Zhong-Yin; Dodd, Garron T.; Tiganis, Tony Trends in Pharmacological Sciences, Vol. 36, Issue 10 https://doi.org/10.1016/j.tips.2015.07.003	journal	October 2015
Structural Basis of Plasticity in Protein Tyrosine Phosphatase 1B Substrate Recognition ^† ^, ^‡ Sarmiento, Mauro; Puius, Yoram A.; Vetter, Stefan W. Biochemistry, Vol. 39, Issue 28 https://doi.org/10.1021/bi000319w	journal	July 2000
HMMER web server: 2015 update Finn, Robert D.; Clements, Jody; Arndt, William Nucleic Acids Research, Vol. 43, Issue W1 https://doi.org/10.1093/nar/gkv397	journal	May 2015
An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering Keedy, Daniel A.; Hill, Zachary B.; Biel, Justin T. eLife, Vol. 7 https://doi.org/10.7554/eLife.36307	journal	June 2018
Correlation between ²H NMR Side-Chain Order Parameters and Sequence Conservation in Globular Proteins Mittermaier, Anthony; Davidson, Alan R.; Kay, Lewis E. Journal of the American Chemical Society, Vol. 125, Issue 30 https://doi.org/10.1021/ja034856q	journal	July 2003
Allosteric inhibition of protein tyrosine phosphatase 1B Wiesmann, Christian; Barr, Kenneth J.; Kung, Jenny Nature Structural & Molecular Biology, Vol. 11, Issue 8 https://doi.org/10.1038/nsmb803	journal	July 2004
Optogenetic Analysis of Allosteric Control in Protein Tyrosine Phosphatases Hongdusit, Akarawin; Fox, Jerome M. Biochemistry, Vol. 60, Issue 4 https://doi.org/10.1021/acs.biochem.0c00841	journal	January 2021
The CCPN data model for NMR spectroscopy: Development of a software pipeline Vranken, Wim F.; Boucher, Wayne; Stevens, Tim J. Proteins: Structure, Function, and Bioinformatics, Vol. 59, Issue 4 https://doi.org/10.1002/prot.20449	journal	April 2005
Retinoic Acid Binding Leads to CRABP2 Rigidification and Dimerization Lixa, Carolina; Clarkson, Michael W.; Iqbal, Anwar Biochemistry, Vol. 58, Issue 41 https://doi.org/10.1021/acs.biochem.9b00672	journal	September 2019
Conformational Motions Regulate Phosphoryl Transfer in Related Protein Tyrosine Phosphatases Whittier, S. K.; Hengge, A. C.; Loria, J. P. Science, Vol. 341, Issue 6148 https://doi.org/10.1126/science.1241735	journal	August 2013
Dynamic activation and regulation of the mitogen-activated protein kinase p38 Kumar, Ganesan Senthil; Clarkson, Michael W.; Kunze, Micha B. A. Proceedings of the National Academy of Sciences, Vol. 115, Issue 18 https://doi.org/10.1073/pnas.1721441115	journal	April 2018
Rational design of allosteric-inhibition sites in classical protein tyrosine phosphatases Chio, Cynthia M.; Yu, Xiaoling; Bishop, Anthony C. Bioorganic & Medicinal Chemistry, Vol. 23, Issue 12 https://doi.org/10.1016/j.bmc.2015.03.027	journal	June 2015
A global analysis of function and conservation of catalytic residues in enzymes Ribeiro, António J. M.; Tyzack, Jonathan D.; Borkakoti, Neera Journal of Biological Chemistry, Vol. 295, Issue 2 https://doi.org/10.1074/jbc.REV119.006289	journal	January 2020

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