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Dynamic Allostery of the Catabolite Activator Protein Revealed by Interatomic Forces

DOI: 10.1371/journal.pcbi.1004358

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Abstract:

The Catabolite Activator Protein (CAP) is a showcase example for entropic allostery. For full activation and DNA binding, the homodimeric protein requires the binding of two cyclic AMP (cAMP) molecules in an anti-cooperative manner, the source of which appears to be largely of entropic nature according to previous experimental studies. We here study at atomic detail the allosteric regulation of CAP with Molecular dynamics (MD) simulations. We recover the experimentally observed entropic penalty for the second cAMP binding event with our recently developed force covariance entropy estimator and reveal allosteric communication pathways with Force Distribution Analyses (FDA). Our observations show that CAP binding results in characteristic changes in the interaction pathways connecting the two cAMP allosteric binding sites with each other, as well as with the DNA binding domains. We identified crucial relays in the mostly symmetric allosteric activation network, and suggest point mutants to test this mechanism. Our study suggests inter-residue forces, as opposed to coordinates, as a highly sensitive measure for structural adaptations that, even though minute, can very effectively propagate allosteric signals.

References

[1]  Heyduk T, Lee JC. Escherichia coli cAMP receptor protein: evidence for three protein conformational states with different promoter binding affinities. Biochemistry (Mosc). 1989;28: 6914–6924. doi: 10.1021/bi00443a021
[2]  Leu S-F, Baker CH, Lee EJ, Harman JG. Position 127 Amino Acid Substitutions Affect the Formation of CRP:cAMP:lacP Complexes but Not CRP:cAMP:RNA Polymerase Complexes at lacP?. Biochemistry (Mosc). 1999;38: 6222–6230. doi: 10.1021/bi982938z
[3]  Takahashi M, Blazy B, Baudras A, Hillen W. Ligand-modulated binding of a gene regulatory protein to DNA: Quantitative analysis of cyclic-AMP induced binding of CRP from Escherichia coli to non-specific and specific DNA targets. J Mol Biol. 1989;207: 783–796. pmid:2547972 doi: 10.1016/0022-2836(89)90244-1
[4]  Parkinson G, Wilson C, Gunasekera A, Ebright YW, Ebright RE, Berman HM. Structure of the CAP-DNA Complex at 2.5 ? Resolution: A Complete Picture of the Protein-DNA Interface. J Mol Biol. 1996;260: 395–408. pmid:8757802 doi: 10.1016/j.jmb.2011.10.002
[5]  Napoli AA, Lawson CL, Ebright RH, Berman HM. Indirect Readout of DNA Sequence at the Primary-kink Site in the CAP–DNA Complex: Recognition of Pyrimidine-Purine and Purine-Purine Steps. J Mol Biol. 2006;357: 173–183. pmid:16427082 doi: 10.1016/j.jmb.2005.12.051
[6]  Chen S, Vojtechovsky J, Parkinson GN, Ebright RH, Berman HM. Indirect readout of DNA sequence at the primary-kink site in the CAP-DNA complex: DNA binding specificity based on energetics of DNA kinking. J Mol Biol. 2001;314: 63–74. d pmid:11724532 doi: 10.1006/jmbi.2001.5089
[7]  Hudson BP, Quispe J, Lara-González S, Kim Y, Berman HM, Arnold E, et al. Three-dimensional EM structure of an intact activator-dependent transcription initiation complex. Proc Natl Acad Sci. 2009;106: 19830–19835. doi: 10.1073/pnas.0908782106. pmid:19903881
[8]  Popovych N, Sun S, Ebright RH, Kalodimos CG. Dynamically driven protein allostery. Nat Struct Mol Biol. 2006;13: 831–838. pmid:16906160 doi: 10.1038/nsmb1132
[9]  Passner JM, Schultz SC, Steitz TA. Modeling the cAMP-induced Allosteric Transition Using the Crystal Structure of CAP-cAMP at 2.1 ? Resolution. J Mol Biol. 2000;304: 847–859. pmid:11124031 doi: 10.1006/jmbi.2000.4231
[10]  Li L, Uversky VN, Dunker AK, Meroueh SO. A Computational Investigation of Allostery in the Catabolite Activator Protein. J Am Chem Soc. 2007;129: 15668–15676. pmid:18041838 doi: 10.1021/ja076046a
[11]  Hilser VJ. Structural biology: Signalling from disordered proteins. Nature. 2013;498: 308–310. doi: 10.1038/498308a. pmid:23783624
[12]  Motlagh HN, Wrabl JO, Li J, Hilser VJ. The ensemble nature of allostery. Nature. 2014;508: 331–339. doi: 10.1038/nature13001. pmid:24740064
[13]  Tzeng S-R, Kalodimos CG. Dynamic activation of an allosteric regulatory protein. Nature. 2009;462: 368–372. doi: 10.1038/nature08560. pmid:19924217
[14]  Zhou J, Bronowska A, Le Coq J, Lietha D, Gr?ter F. Allosteric Regulation of Focal Adhesion Kinase by PIP2 and ATP. Biophys J. 2015;108: 698–705. doi: 10.1016/j.bpj.2014.11.3454
[15]  Stacklies W, Seifert C, Graeter F. Implementation of force distribution analysis for molecular dynamics simulations. BMC Bioinformatics. 2011;12: 101. doi: 10.1186/1471-2105-12-101. pmid:21501475
[16]  Costescu BI, Grater F. Time-resolved force distribution analysis. BMC Biophys. 2013;6: 5. doi: 10.1186/2046-1682-6-5. pmid:24499624
[17]  Gilson MK. Stress Analysis at the Molecular Level: A Forced Cucurbituril-Guest Dissociation Pathway. J Chem Theory Comput. 2010;6: 637–646. pmid:23794959 doi: 10.1021/ct900668k
[18]  Koike K, Kawaguchi K, Yamato T. Stress tensor analysis of the protein quake of photoactive yellow protein. Phys Chem Chem Phys. 2008;10: 1400–1405. doi: 10.1039/b714618c. pmid:18309395
[19]  Palmai Z, Seifert C, Gr?ter F, Balog E. An allosteric signaling pathway of human 3-phosphoglycerate kinase from force distribution analysis. PLoS Comput Biol. 2014;10: e1003444. doi: 10.1371/journal.pcbi.1003444. pmid:24465199
[20]  Seifert C, Gr?ter F. Force Distribution Reveals Signal Transduction in E. coli Hsp90. Biophys J. 2012;103: 2195–2202. doi: 10.1016/j.bpj.2012.09.008. pmid:23200053
[21]  Stacklies W, Xia F, Gr?ter F. Dynamic allostery in the methionine repressor revealed by force distribution analysis. PLoS Comput Biol. 2009;5: e1000574. doi: 10.1371/journal.pcbi.1000574. pmid:19936294
[22]  Hu H, Hermans J, Lee AL. Relating side-chain mobility in proteins to rotameric transitions: Insights from molecular dynamics simulations and NMR. J Biomol NMR. 2005;32: 151–162. pmid:16034666 doi: 10.1007/s10858-005-5366-0
[23]  Tzeng S-R, Kalodimos CG. Protein activity regulation by conformational entropy. Nature. 2012;488: 236–240. doi: 10.1038/nature11271. pmid:22801505
[24]  Kasinath V, Sharp KA, Wand AJ. Microscopic insights into the NMR relaxation-based protein conformational entropy meter. J Am Chem Soc. 2013;135: 15092–15100. doi: 10.1021/ja405200u. pmid:24007504
[25]  Popovych N, Tzeng S-R, Tonelli M, Ebright RH, Kalodimos CG. Structural basis for cAMP-mediated allosteric control of the catabolite activator protein. Proc Natl Acad Sci U S A. 2009;106: 6927–6932. doi: 10.1073/pnas.0900595106. pmid:19359484
[26]  Schultz SC, Shields GC, Steitz TA. Crystal structure of a CAP-DNA complex: the DNA is bent by 90 degrees. Science. 1991;253: 1001–1007. pmid:1653449 doi: 10.1126/science.1653449
[27]  Chu SY, Tordova M, Gilliland GL, Gorshkova I, Shi Y, Wang S, et al. The Structure of the T127L/S128A Mutant of cAMP Receptor Protein Facilitates Promoter Site Binding. J Biol Chem. 2001;276: 11230–11236. pmid:11124966 doi: 10.1074/jbc.m010428200
[28]  Parkinson G, Gunasekera A, Vojtechovsky J, Zhang X, Kunkel TA, Berman H, et al. Aromatic hydrogen bond in sequence-specific protein DNA recognition. Nat Struct Biol. 1996;3: 837–841. pmid:8836098 doi: 10.1038/nsb1096-837
[29]  Tao W, Gao Z, Gao Z, Zhou J, Huang Z, Dong Y, et al. The 1.6 ? resolution structure of activated D138L mutant of catabolite gene activator protein with two cAMP bound in each monomer. Int J Biol Macromol. 2011;48: 459–465. doi: 10.1016/j.ijbiomac.2011.01.009. pmid:21255606
[30]  Hensen U, Gr?ter F, Henchman RH. Macromolecular Entropy Can Be Accurately Computed from Force. J Chem Theory Comput. 2014;10: 4777–4781. doi: 10.1021/ct500684w
[31]  Karplus M, Kushick JN. Method for estimating the configurational entropy of macromolecules. Macromolecules. 1981;14: 325–332. doi: 10.1021/ma50003a019
[32]  Belduz AO, Lee EJ, Harman JG. Mutagenesis of the cyclic AMP receptor protein of Escherichia coli targeting positions 72 and 82 of the cyclic nucleotide binding pocket. Nucleic Acids Res. 1993;21: 1827–1835. pmid:8388097 doi: 10.1093/nar/21.8.1827
[33]  Moore J, Kantorow M, Vanderzwaag D, McKenney K. Escherichia coli cyclic AMP receptor protein mutants provide evidence for ligand contacts important in activation. J Bacteriol. 1992;174: 8030–8035. pmid:1334069
[34]  Tzeng S-R, Kalodimos CG. Allosteric inhibition through suppression of transient conformational states. Nat Chem Biol. 2013;9: 462–465. doi: 10.1038/nchembio.1250. pmid:23644478
[35]  Kaledin M, Brown A, Kaledin AL, Bowman JM. Normal mode analysis using the driven molecular dynamics method. II. An application to biological macromolecules. J Chem Phys. 2004;121: 5646–5653. pmid:15366988 doi: 10.1063/1.1777573
[36]  Jose PP, Andricioaei I. Similarities between protein folding and granular jamming. Nat Commun. 2012;3: 1161. doi: 10.1038/ncomms2177. pmid:23093180
[37]  Hess B, Kutzner C, van der Spoel D, Lindahl E. GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. J Chem Theory Comput. 2008;4: 435–447. doi: 10.1021/ct700301q
[38]  Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, et al. A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput Chem. 2003;24: 1999–2012. pmid:14531054 doi: 10.1002/jcc.10349
[39]  Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA. Development and testing of a general amber force field. J Comput Chem. 2004;25: 1157–1174. pmid:15116359 doi: 10.1002/jcc.20035
[40]  Wang J, Wang W, Kollman P, Case D. Automatic atom type and bond type perception in molecular mechanical calculations. J Mol Graph Model. 2006;25: 247–260. pmid:16458552 doi: 10.1016/j.jmgm.2005.12.005
[41]  Vriend G. WHAT IF: A molecular modeling and drug design program. J Mol Graph. 1990;8: 52–56. pmid:2268628 doi: 10.1016/0263-7855(90)80070-v
[42]  Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys. 1983;79: 926–935. doi: 10.1063/1.445869
[43]  Hess B, Bekker H, Berendsen HJC, Fraaije JGEM. LINCS: A linear constraint solver for molecular simulations. J Comput Chem. 1997;18: 1463–1472. doi: 10.1002/(sici)1096-987x(199709)18:12<1463::aid-jcc4>3.3.co;2-l
[44]  Darden T, York D, Pedersen L. Particle mesh Ewald: An N?log(N) method for Ewald sums in large systems. J Chem Phys. 1993;98: 10089–10092. doi: 10.1063/1.464397
[45]  Louet M, Perahia D, Martinez J, Floquet N. A concerted mechanism for opening the GDP binding pocket and release of the nucleotide in hetero-trimeric G-proteins. J Mol Biol. 2011;411: 298–312. doi: 10.1016/j.jmb.2011.05.034. pmid:21663745
[46]  Louet M, Karakas E, Perret A, Perahia D, Martinez J, Floquet N. Conformational restriction of G-proteins Coupled Receptors (GPCRs) upon complexation to G-proteins: A putative activation mode of GPCRs? FEBS Lett. 2013;587: 2656–2661. doi: 10.1016/j.febslet.2013.06.052. pmid:23851072
[47]  Pronk S, Páll S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, et al. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics. 2013;29: 845–854. doi: 10.1093/bioinformatics/btt055. pmid:23407358
[48]  Van der Spoel D, Berendsen HJ. Molecular dynamics simulations of Leu-enkephalin in water and DMSO. Biophys J. 1997;72: 2032–2041. pmid:9129806 doi: 10.1016/s0006-3495(97)78847-7

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