Abstract
Allostery is the process by which biological macromolecules (mostly proteins) transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity. Recent experimental observations demonstrating that allostery can be facilitated by dynamic and intrinsically disordered proteins have resulted in a new paradigm for understanding allosteric mechanisms, which focuses on the conformational ensemble and the statistical nature of the interactions responsible for the transmission of information. Analysis of allosteric ensembles reveals a rich spectrum of regulatory strategies, as well as a framework to unify the description of allosteric mechanisms from different systems.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Monod, J. & Jacob, F. Teleonomic mechanisms in cellular metabolism, growth, and differentiation. Cold Spring Harb. Symp. Quant. Biol. 26, 389–401 (1961)
Changeux, J. P. The feedback control mechanisms of biosynthetic L-threonine deaminase by L-isoleucine. Cold Spring Harb. Symp. Quant. Biol. 26, 313–318 (1961)
Monod, J., Wyman, J. & Changeux, J. P. On the nature of allosteric transitions: a plausible model. J. Mol. Biol. 12, 88–118 (1965)
Freiburger, L. A. et al. Competing allosteric mechanisms modulate substrate binding in a dimeric enzyme. Nature Struct. Mol. Biol. 18, 288–294 (2011)
Nussinov, R., Tsai, C. J. & Ma, B. The (still) underappreciated role of allostery in the cellular network. Annu. Rev. Biophys. 42, 169–189 (2013)
Monod, J. Chance and Necessity: Essay on the Natural Philosophy of Modern Biology (Penguin Books, 1977)
Fenton, A. W. Allostery: an illustrated definition for the “second secret of life”. Trends Biochem. Sci. 33, 420–425 (2008)
Hilser, V. J., Wrabl, J. O. & Motlagh, H. N. Structural and energetic basis of allostery. Ann. Rev. Biophys. 41, 585–609 (2012)
Perutz, M. F. et al. Structure of haemoglobin: a three-dimensional Fourier synthesis at 5.5-Å resolution, obtained by X-ray analysis. Nature 185, 416–422 (1960)
Perutz, M. F. Stereochemistry of cooperative effects in haemoglobin. Nature 228, 726–734 (1970)
Dickerson, R. E. X-ray studies of protein mechanisms. Annu. Rev. Biophys. Chem. 41, 815–842 (1972)
Laskowski, R. A., Gerick, F. & Thornton, J. M. The structural basis of allosteric regulation in proteins. FEBS Lett. 583, 1692–1698 (2009)
Perutz, M. F., Wilkinson, A. J., Paoli, M. & Dodson, G. G. The stereochemical mechanism of the cooperative effects in hemoglobin revisited. Annu. Rev. Biophys. Biomol. Struct. 27, 1–34 (1998)
Changeux, J. P. & Edelstein, S. J. Allosteric mechanisms of signal transduction. Science 308, 1424–1428 (2005)
Gunasekaran, K., Ma, B. & Nussinov, R. Is allostery an intrinsic property of all dynamic proteins? Proteins Struct. Funct. Bioinf. 57, 433–443 (2004)
Tzeng, S. R. & Kalodimos, C. G. Protein dynamics and allostery: an NMR view. Curr. Opin. Struct. Biol. 21, 62–67 (2011)
Kern, D. & Zuiderweg, E. R. The role of dynamics in allosteric regulation. Curr. Opin. Struct. Biol. 13, 748–757 (2003)
Smock, R. G. & Gierasch, L. M. Sending signals dynamically. Science 324, 198–203 (2009)
Tsai, C. J., del Sol, A. & Nussinov, R. Protein allostery, signal transmission and dynamics: a classification scheme of allosteric mechanisms. Mol. Biosyst. 5, 207–216 (2009)
Daily, M. D. & Gray, J. J. Allosteric communication occurs via networks of tertiary and quaternary motions in proteins. PLOS Comput. Biol. 5, e1000293 (2009)
Swain, J. F. et al. Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker. Mol. Cell 26, 27–39 (2007)
Zuiderweg, E. R. et al. Allostery in the Hsp70 chaperone proteins. Top. Curr. Chem. 328, 99–153 (2013)
Petit, C. M., Zhang, J., Sapienza, P. J., Fuentes, E. J. & Lee, A. L. Hidden dynamic allostery in a PDZ domain. Proc. Natl Acad. Sci. USA 106, 18249–18254 (2009)
Tzeng, S. R. & Kalodimos, C. G. Protein activity regulation by conformational entropy. Nature 488, 236–240 (2012)
Tzeng, S. R. & Kalodimos, C. G. Dynamic activation of an allosteric regulatory protein. Nature 462, 368–372 (2009)
Popovych, N., Sun, S., Ebright, R. H. & Kalodimos, C. G. Dynamically driven protein allostery. Nature Struct. Mol. Biol. 13, 831–838 (2006)The first experimental demonstrations of dynamically mediated protein allostery in the CAP using relaxation dispersion NMR and NMR-detected hydrogen exchange.
Reichheld, S. E., Yu, Z. & Davidson, A. R. The induction of folding cooperativity by ligand binding drives the allosteric response of tetracycline repressor. Proc. Natl Acad. Sci. USA 106, 22263–22268 (2009)
Garcia-Pino, A. et al. Allostery and intrinsic disorder mediate transcription regulation by conditional cooperativity. Cell 142, 101–111 (2010)This article demonstrates how increasing the relative concentration of one ligand can result in conditional cooperativity in an intrinsically disordered protein; in other words, the same protein can initially be an on-switch but then an off-switch at higher concentrations.
Sevcsik, E., Trexler, A. J., Dunn, J. M. & Rhoades, E. Allostery in a disordered protein: oxidative modifications to α-synuclein act distally to regulate membrane binding. J. Am. Chem. Soc. 133, 7152–7158 (2011)
Ferreon, A. C. M., Ferreon, J. C., Wright, P. E. & Deniz, A. A. Modulation of allostery by protein intrinsic disorder. Nature 498, 390–394 (2013)This article directly demonstrates cooperative ‘switching’ behaviour in an intrinsically disordered protein, via allosteric effects from truncation of the amino acid sequence.
Monod, J., Changeux, J. P. & Jacob, F. Allosteric proteins and cellular control systems. J. Mol. Biol. 6, 306–329 (1963)
Koshland, D. E., Nemethy, G. & Filmer, D. Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry 5, 365–385 (1966)
Cui, Q. & Karplus, M. Allostery and cooperativity revisited. Protein Sci. 17, 1295–1307 (2008)A thoughtful, comprehensive review that synthesizes the ‘old’ and ‘new’ views of allostery with experimental and computational case studies from the literature.
Koshland, D. E. Enzyme flexibility and enzyme action. J. Cell. Comp. Physiol. 54, 245–258 (1959)
Whitley, M. J. & Lee, A. L. Frameworks for understanding long-range intra-protein communication. Curr. Protein Pept. Sci. 10, 116–127 (2009)
Changeux, J. P. Allostery and the Monod–Wyman–Changeux model after 50 years. Ann. Rev. Biophys. 41, 103–133 (2012)
Eaton, W. A. et al. Evolution of allosteric models for hemoglobin. IUBMB Life 59, 586–599 (2007)
Eaton, W. A., Henry, E. R., Hofrichter, J. & Mozzarelli, A. Is cooperative oxygen binding by hemoglobin really understood? Nature Struct. Biol. 6, 351–358 (1999)
Erman, B. A fast approximate method of identifying paths of allosteric communication in proteins. Proteins Struct. Funct. Bioinf. 81, 1097–1101 (2013)
Tang, S. et al. Predicting allosteric communication in myosin via a pathway of conserved residues. J. Mol. Biol. 373, 1361–1373 (2007)
England, J. L. Allostery in protein domains reflects a balance of steric and hydrophobic effects. Structure 19, 967–975 (2011)
VanWart, A. T., Eargle, J., Luthey-Schulten, Z. & Amaro, R. E. Exploring residue component contributions to dynamical network models of allostery. J. Chem. Theory Comput. 8, 2949–2961 (2012)
Lockless, S. W. & Ranganathan, R. Evolutionarily conserved pathways of energetic connectivity in protein families. Science 286, 295–299 (1999)
Süel, G. M., Lockless, S. W., Wall, M. A. & Ranganathan, R. Evolutionarily conserved networks of residues mediate allosteric communication in proteins. Nature Struct. Biol. 10, 59–69 (2003)
Colombo, M. F., Rau, D. C. & Parsegian, V. A. Protein solvation in allosteric regulation: a water effect on hemoglobin. Science 256, 655–659 (1992)Groundbreaking experimental work demonstrating the large energetic effects of hydration on haemoglobin conformation and thus protein allostery.
Elber, R. Simulations of allosteric transitions. Curr. Opin. Struct. Biol. 21, 167–172 (2011)
Weinkam, P., Chen, Y. C., Pons, J. & Sali, A. Impact of mutations on the allosteric conformational equilibrium. J. Mol. Biol. 425, 647–661 (2013)
Marcos, E., Crehuet, R. & Bahar, I. Changes in dynamics upon oligomerization regulate substrate binding and allostery in amino acid kinase family members. PLOS Comput. Biol. 7, e1002201 (2011)
Silva, M. M., Rogers, P. H. & Arnone, A. A third quaternary structure of human hemoglobin A at 1.7-Å resolution. J. Biol. Chem. 267, 17248–17256 (1992)
Cooper, A. & Dryden, D. T. F. Allostery without conformational change. Eur. Biophys. J. 11, 103–109 (1984)The first explicit articulation of dynamic allostery, demonstrating the theoretical relevance of an entirely entropic energetic contribution to biological function.
Fraser, J. S. et al. Hidden alternative structures of proline isomerase essential for catalysis. Nature 462, 669–673 (2009)
Lukin, J. A. et al. Quaternary structure of hemoglobin in solution. Proc. Natl Acad. Sci. USA 100, 517–520 (2003)
Sekhar, A. & Kay, L. E. NMR paves the way for atomic level descriptions of sparsely populated, transiently formed biomolecular conformers. Proc. Natl Acad. Sci. USA 110, 12867–12874 (2013)
Wand, A. J. The dark energy of proteins comes to light: conformational entropy and its role in protein function revealed by NMR relaxation. Curr. Opin. Struct. Biol. 23, 75–81 (2013)
Manley, G., Rivalta, I. & Loria, J. P. Solution NMR and computational methods for understanding protein allostery. J. Phys. Chem. B 117, 3063–3073 (2013)
Liu, J. et al. Intrinsic disorder in transcription factors. Biochemistry 45, 6873–6888 (2006)
Uversky, V. N. Intrinsically disordered proteins from A to Z. Int. J. Biochem. Cell Biol. 43, 1090–1103 (2011)
Uversky, V. N., Oldfield, C. J. & Dunker, A. K. Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling. J. Mol. Recognit. 18, 343–384 (2005)
Wright, P. E. Intrinsically unstructured proteins: re-assessing the structure-function paradigm. J. Mol. Biol. 293, 321–331 (1999)
Tompa, P. Unstructural biology coming of age. Curr. Opin. Struct. Biol. 21, 419–425 (2011)
Hilser, V. J. & Thompson, E. B. Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins. Proc. Natl Acad. Sci. USA 104, 8311–8315 (2007)The first paper to propose and demonstrate that intrinsic disorder can be used by proteins to mediate allosteric coupling.
Luque, I. & Freire, E. Structural parameterization of the binding enthalpy of small ligands. Proteins 49, 181–190 (2002)
Li, Z., Raychaudhuri, S. & Wand, A. J. Insights into the local residual entropy of proteins provided by NMR relaxation. Protein Sci. 5, 2647–2650 (1996)
Yang, D. & Kay, L. E. Contributions to conformational entropy arising from bond vector fluctuations measured from NMR-derived order parameters: application to protein folding. J. Mol. Biol. 263, 369–382 (1996)
Igumenova, T. I., Frederick, K. K. & Wand, A. J. Characterization of the fast dynamics of protein amino acid side chains using NMR relaxation in solution. Chem. Rev. 106, 1672–1699 (2006)
Jarymowycz, V. A. & Stone, M. J. Fast time scale dynamics of protein backbones: NMR relaxation methods, applications, and functional consequences. Chem. Rev. 106, 1624–1671 (2006)
Frederick, K. K., Marlow, M. S., Valentine, K. G. & Wand, A. J. Conformational entropy in molecular recognition by proteins. Nature 448, 325–329 (2007)
Lee, A. L., Kinnear, S. A. & Wand, A. J. Redistribution and loss of side chain entropy upon formation of a calmodulin–peptide complex. Nature Struct. Biol. 7, 72–77 (2000)
Palmer, A. G., Kroenke, C. D. & Loria, J. P. Nuclear magnetic resonance methods for quantifying microsecond-to-millisecond motions in biological macromolecules. Methods Enzymol. 339, 204–238 (2001)
Marlow, M. S., Dogan, J., Frederick, K. K., Valentine, K. G. & Wand, A. J. The role of conformational entropy in molecular recognition by calmodulin. Nature Chem. Biol. 6, 352–358 (2010)
Igumenova, T. I., Lee, A. L. & Wand, A. J. Backbone and side chain dynamics of mutant calmodulin–peptide complexes. Biochemistry 44, 12627–12639 (2005)
Laine, O., Streaker, E. D., Nabavi, M., Fenselau, C. C. & Beckett, D. Allosteric signaling in the biotin repressor occurs via local folding coupled to global dampening of protein dynamics. J. Mol. Biol. 381, 89–101 (2008)
Rodgers, T. L. et al. Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors. PLoS Biol. 11, e1001651 (2013)
Schrank, T. P., Bolen, D. W. & Hilser, V. J. Rational modulation of conformational fluctuations in adenylate kinase reveals a local unfolding mechanism for allostery and functional adaptation in proteins. Proc. Natl Acad. Sci. USA 106, 16984–16989 (2009)
Gao, J. & Xu, D. Correlation between posttranslational modification and intrinsic disorder in protein. Pac. Symp. Biocomput. 94–103 (2012)
Romero, P. R. et al. Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc. Natl Acad. Sci. USA 103, 8390–8395 (2006)
Frauenfelder, H., Sligar, S. G. & Wolynes, P. G. The energy landscapes and motions of proteins. Science 254, 1598–1603 (1991)
Dill, K. A. & Chan, H. S. From Levinthal to pathways to funnels. Nature Struct. Biol. 4, 10–19 (1997)
Onuchic, J. N., Luthey-Schulten, Z. & Wolynes, P. G. Theory of protein folding: the energy landscape perspective. Annu. Rev. Phys. Chem. 48, 545–600 (1997)
Pan, H., Lee, J. C. & Hilser, V. J. Binding sites in Escherichia coli dihydrofolate reductase communicate by modulating the conformational ensemble. Proc. Natl Acad. Sci. USA 97, 12020–12025 (2000)
Bray, D. & Duke, T. A. Conformational spread: the propagation of allosteric states in large multiprotein complexes. Annu. Rev. Biophys. Biomol. Struct. 33, 53–73 (2004)
Luque, I., Leavitt, S. A. & Freire, E. The linkage between protein folding and functional cooperativity: two sides of the same coin? Annu. Rev. Biophys. Biomol. Struct. 31, 235–256 (2002)
Ackers, G. K., Johnson, A. D. & Shea, M. A. Quantitative model for gene regulation by the lambda phage repressor. Proc. Natl Acad. Sci. USA 79, 1129–1133 (1982)
Motlagh, H. N. & Hilser, V. J. Agonsim/antagonism switching in allosteric ensembles. Proc. Natl Acad. Sci. USA 109, 4134–4139 (2012)
Bai, F. et al. Conformational spread as a mechanism for cooperativity in the bacterial flagellar switch. Science 327, 685–689 (2010)
Gekko, K., Obu, N., Li, J. & Lee, J. C. A linear correlation between the energetics of allosteric communication and protein flexibility in the Escherichia coli cyclic AMP receptor protein revealed by mutation-induced changes in compressibility and amide hydrogen-deuterium exchange. Biochemistry 43, 3844–3852 (2004)
Fisher, C. K. & Stultz, C. M. Constructing ensembles for intrinsically disordered proteins. Curr. Opin. Struct. Biol. 21, 426–431 (2011)
Forman-Kay, J. D. & Mittag, T. From sequence and forces to structure, function, and evolution of intrinsically disordered proteins. Structure 21, 1492–1499 (2013)
Mittag, T. & Forman-Kay, J. D. Atomic-level characterization of disordered protein ensembles. Curr. Opin. Struct. Biol. 17, 3–14 (2007)
Bernadó, P. et al. A structural model for unfolded proteins from residual dipolar couplings and small-angle x-ray scattering. Proc. Natl Acad. Sci. USA 102, 17002–17007 (2005)
Jensen, M. R. et al. Quantitative determination of the conformational properties of partially folded and intrinsically disordered proteins using NMR dipolar couplings. Structure 17, 1169–1185 (2009)
Cavalli, A., Salvatella, X., Dobson, C. M. & Vendruscolo, M. Protein structure determination from NMR chemical shifts. Proc. Natl Acad. Sci. USA 104, 9615–9620 (2007)
Clore, G. M. Visualizing lowly-populated regions of the free energy landscape of macromolecular complexes by paramagnetic relaxation enhancement. Mol. Biosyst. 4, 1058–1069 (2008)
Lindorff-Larsen, K., Best, R. B., Depristo, M. A., Dobson, C. M. & Vendruscolo, M. Simultaneous determination of protein structure and dynamics. Nature 433, 128–132 (2005)
Tang, C., Louis, J. M., Aniana, A., Suh, J. Y. & Clore, G. M. Visualizing transient events in amino-terminal autoprocessing of HIV-1 protease. Nature 455, 693–696 (2008)
Yu, B. et al. Structural and energetic mechanisms of cooperative autoinhibition and activation of Vav1. Cell 140, 246–256 (2010)
Fraser, J. S. et al. Accessing protein conformational ensembles using room-temperature X-ray crystallography. Proc. Natl Acad. Sci. USA 108, 16247–16252 (2011)
Burnley, T. B., Afonine, P. V., Adams, P. D. & Gros, P. Modelling dynamics in protein crystal structures by ensemble refinement. eLife 1, e00311 (2012)
Penczek, P. A., Kimmel, M. & Spahn, C. M. T. Identifying conformational states of macromolecules by eigen-analysis of resampled cryo-EM images. Structure 19, 1582–1590 (2011)
Dror, R. O., Dirks, R. M., Grossman, J. P., Xu, H. & Shaw, D. E. Biomolecular simulation: a computational microscope for molecular biology. Annu. Rev. Biophys. 41, 429–452 (2012)
Dror, R. O. et al. Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature 503, 295–299 (2013)
Qian, H. Cyclic conformational modification of an enzyme: serial engagement, energy relay, hysteretic enzyme, and Fischer’s hypothesis. J. Phys. Chem. B 114, 16105–16111 (2010)
Ward, A. B., Sali, A. & Wilson, I. A. Integrative structural biology. Science 339, 913–915 (2013)
Andreeva, A. et al. Data growth and its impact on the SCOP database: new developments. Nucleic Acids Res. 36, D419–D425 (2008)
Cesareni, G., Gimona, M., Sudol, M. & Yaffe, M. Modular Protein Domains (Wiley-VCH, 2005)
Loh, S. N. & Ha, J. H. Protein conformational switches: from nature to design. Chemistry 18, 7984–7999 (2012)
Choi, J. H., San, A. & Ostermeier, M. Non-allosteric enzyme switches possess larger effector-induced changes in thermodynamic stability than their non-switch analogs. Protein Sci. 22, 475–485 (2013)
Zayner, J. P., Antoniou, C., French, A. R., Hause, R. J., Jr & Sosnick, T. R. Investigating models of protein function and allostery with a widespread mutational analysis of a light activated protein. Biophys. J. 105, 1027–1036 (2013)
Acknowledgements
This work was supported by National Science Foundation grant MCB1330211 and by National Institutes of Health grants GM63747 and T32-GM008403.
Author information
Authors and Affiliations
Contributions
V.J.H. conceived the manuscript; H.N.M., J.O.W., J.L. and V.J.H. wrote and edited the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Motlagh, H., Wrabl, J., Li, J. et al. The ensemble nature of allostery. Nature 508, 331–339 (2014). https://doi.org/10.1038/nature13001
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature13001
This article is cited by
-
Design of inhibitor peptide sequences based on the interfacial knowledge of the protein G-IgG crystallographic complex and their binding studies with IgG
European Biophysics Journal (2024)
-
Switching imidazole reactivity by dynamic control of tautomer state in an allosteric foldamer
Nature Communications (2023)
-
Preferential molecular recognition of heterochiral guests within a cyclophane receptor
Nature Communications (2023)
-
Allosteric control of olefin isomerization kinetics via remote metal binding and its mechanochemical analysis
Nature Communications (2023)
-
ABC transporters are billion-year-old Maxwell Demons
Communications Physics (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.