Role of Conformational Entropy in the Activity and Regulation of the Catalytic Subunit of Protein Kinase A

Overview

Journal FEBS J

Specialty Biochemistry

Date 2013 Aug 2

PMID 23902454

Citations 12

Authors

Gianluigi Veglia

Alessandro Cembran

Affiliations

Soon will be listed here.

Abstract

Protein kinase A (PKA) is the archetypical phosphokinase, sharing a catalytic core with the entire protein kinase superfamily. In eukaryotes, the ubiquitous location of PKA makes it one of the most important cellular signaling molecules, involved in a myriad of events. The catalytic subunit of PKA (PKA-C) is one of the most studied enzymes and was the first kinase to be crystallized; however, the effects of ligand binding, post-translational modifications and mutations on the activity of the kinase have been difficult to understand with only structural data. Here, we review our latest NMR studies on PKA-C, the results of which underscore the role of fast and slow conformational dynamics in the activation and inhibition of the kinase.

Citing Articles

The "violin model": Looking at community networks for dynamic allostery.

Madan L, Welsh C, Kornev A, Taylor S J Chem Phys. 2023; 158(8):081001.

PMID: 36859094 PMC: 9957607. DOI: 10.1063/5.0138175.

Loosening of Side-Chain Packing Associated with Perturbations in Peripheral Dynamics Induced by the D76N Mutation of β-Microglobulin Revealed by Pressure-NMR and Molecular Dynamic Simulations.

Sakurai K, Tomiyama R, Shiraki T, Yonezawa Y Biomolecules. 2019; 9(9).

PMID: 31527472 PMC: 6769805. DOI: 10.3390/biom9090491.

Integrin α9 depletion promotes β-catenin degradation to suppress triple-negative breast cancer tumor growth and metastasis.

Wang Z, Li Y, Xiao Y, Lin H, Yang P, Humphries B Int J Cancer. 2019; 145(10):2767-2780.

PMID: 31008533 PMC: 6750961. DOI: 10.1002/ijc.32359.

Increased thrombospondin-4 after nerve injury mediates disruption of intracellular calcium signaling in primary sensory neurons.

Guo Y, Zhang Z, Wu H, Luo Z, Hogan Q, Pan B Neuropharmacology. 2017; 117:292-304.

PMID: 28232180 PMC: 5414309. DOI: 10.1016/j.neuropharm.2017.02.019.

Mutation of a kinase allosteric node uncouples dynamics linked to phosphotransfer.

Ahuja L, Kornev A, McClendon C, Veglia G, Taylor S Proc Natl Acad Sci U S A. 2017; 114(6):E931-E940.

PMID: 28115705 PMC: 5307475. DOI: 10.1073/pnas.1620667114.

References

Wang C, Rance M, Palmer 3rd A . Mapping chemical exchange in proteins with MW > 50 kD. J Am Chem Soc. 2004; 125(30):8968-9. DOI: 10.1021/ja035139z. View

Manning G, Whyte D, Martinez R, Hunter T, Sudarsanam S . The protein kinase complement of the human genome. Science. 2002; 298(5600):1912-34. DOI: 10.1126/science.1075762. View

Igumenova T, Frederick K, Wand A . Characterization of the fast dynamics of protein amino acid side chains using NMR relaxation in solution. Chem Rev. 2006; 106(5):1672-99. PMC: 2547146. DOI: 10.1021/cr040422h. View

Boehr D, Dyson H, Wright P . An NMR perspective on enzyme dynamics. Chem Rev. 2006; 106(8):3055-79. DOI: 10.1021/cr050312q. View

Boehr D, McElheny D, Dyson H, Wright P . The dynamic energy landscape of dihydrofolate reductase catalysis. Science. 2006; 313(5793):1638-42. DOI: 10.1126/science.1130258. View

Johnson L, Lowe E, Noble M, Owen D . The Eleventh Datta Lecture. The structural basis for substrate recognition and control by protein kinases. FEBS Lett. 1998; 430(1-2):1-11. DOI: 10.1016/s0014-5793(98)00606-1. View

Abu-Abed M, Das R, Wang L, Melacini G . Definition of an electrostatic relay switch critical for the cAMP-dependent activation of protein kinase A as revealed by the D170A mutant of RIalpha. Proteins. 2007; 69(1):112-24. DOI: 10.1002/prot.21446. View

Masterson L, Cembran A, Shi L, Veglia G . Allostery and binding cooperativity of the catalytic subunit of protein kinase A by NMR spectroscopy and molecular dynamics simulations. Adv Protein Chem Struct Biol. 2012; 87:363-89. PMC: 3546502. DOI: 10.1016/B978-0-12-398312-1.00012-3. View

Tzeng S, Kalodimos C . Protein activity regulation by conformational entropy. Nature. 2012; 488(7410):236-40. DOI: 10.1038/nature11271. View

10.

Baldwin A, Kay L . NMR spectroscopy brings invisible protein states into focus. Nat Chem Biol. 2009; 5(11):808-14. DOI: 10.1038/nchembio.238. View

11.

Verardi R, Shi L, Traaseth N, Walsh N, Veglia G . Structural topology of phospholamban pentamer in lipid bilayers by a hybrid solution and solid-state NMR method. Proc Natl Acad Sci U S A. 2011; 108(22):9101-6. PMC: 3107283. DOI: 10.1073/pnas.1016535108. View

12.

Ishima R, Torchia D . Protein dynamics from NMR. Nat Struct Biol. 2000; 7(9):740-3. DOI: 10.1038/78963. View

13.

Kornev A, Taylor S, Ten Eyck L . A helix scaffold for the assembly of active protein kinases. Proc Natl Acad Sci U S A. 2008; 105(38):14377-82. PMC: 2533684. DOI: 10.1073/pnas.0807988105. View

14.

Johnson D, Akamine P, Radzio-Andzelm E, Madhusudan M, Taylor S . Dynamics of cAMP-dependent protein kinase. Chem Rev. 2001; 101(8):2243-70. DOI: 10.1021/cr000226k. View

15.

McNicholl E, Das R, SilDas S, Taylor S, Melacini G . Communication between tandem cAMP binding domains in the regulatory subunit of protein kinase A-Ialpha as revealed by domain-silencing mutations. J Biol Chem. 2010; 285(20):15523-15537. PMC: 2865341. DOI: 10.1074/jbc.M110.105783. View

16.

Pisliakov A, Cao J, Kamerlin S, Warshel A . Enzyme millisecond conformational dynamics do not catalyze the chemical step. Proc Natl Acad Sci U S A. 2009; 106(41):17359-64. PMC: 2762662. DOI: 10.1073/pnas.0909150106. View

17.

Traaseth N, Ha K, Verardi R, Shi L, Buffy J, Masterson L . Structural and dynamic basis of phospholamban and sarcolipin inhibition of Ca(2+)-ATPase. Biochemistry. 2007; 47(1):3-13. PMC: 2699759. DOI: 10.1021/bi701668v. View

18.

Kumar S, Ma B, Tsai C, Sinha N, Nussinov R . Folding and binding cascades: dynamic landscapes and population shifts. Protein Sci. 2000; 9(1):10-9. PMC: 2144430. DOI: 10.1110/ps.9.1.10. View

19.

Labeikovsky W, Eisenmesser E, Bosco D, Kern D . Structure and dynamics of pin1 during catalysis by NMR. J Mol Biol. 2007; 367(5):1370-81. PMC: 2975599. DOI: 10.1016/j.jmb.2007.01.049. View

20.

Palmer 3rd A . Nmr probes of molecular dynamics: overview and comparison with other techniques. Annu Rev Biophys Biomol Struct. 2001; 30:129-55. DOI: 10.1146/annurev.biophys.30.1.129. View