Ensemble-Based Analysis of the Dynamic Allostery in the PSD-95 PDZ3 Domain in Relation to the General Variability of PDZ Structures
Abstract
:1. Introduction
2. Results
2.1. The Calculated PDZ3 Ensembles Reflect Experimental Backbone and Side-Chain S Order Parameters
2.2. Estimates of Changes in Conformational Entropy upon Binding Are Consistent with Experimental Observations
2.3. Principal Component Analysis Reveals Distinct Motional Modes Affecting the Ligand Binding Site in PDZ3
2.4. Residue–Residue Contacts Affected by the Motions and the Presence of Helix 3 and the Ligand
2.5. Comparison of PSD-95 PDZ3 with an Extended Set of PDZ Domains
2.6. The Three PDZ Domains of PSD-95
2.7. Comparison of the Free and Complexed States of Different PDZ Domains
3. Discussion
3.1. The PDZ3 Ensembles as Models to Describe Internal Motions
3.2. PDZ3 Internal Motions and Their Modulation
3.3. Motions in the Light of Other PDZ Domain Structures
3.4. Common Motifs and Unique Properties of PDZ Domains Relative to PSD-95 PDZ3
4. Materials and Methods
4.1. Datasets and Structures
4.2. Restrained Molecular Dynamics Simulations
4.3. Generation of Small Ensembles with Chemical Shift-Based Selection
4.4. Conformational Entropy Calculations
4.5. Analysis of the Ensembles
4.6. Comparative Analysis of a Large Set of PDZ Domains/Ensembles
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
MD | molecular dynamics |
PSD-95 | Postsynaptic Density Protein-95 |
PC | Principal component |
PCA | Principal component analysis |
References
- Dosemeci, A.; Weinberg, R.J.; Reese, T.S.; Tao-Cheng, J.-H. The postsynaptic density: There is more than meets the eye. Front. Synaptic Neurosci. 2016, 8, 23. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dosemeci, A.; Makusky, A.J.; Jankowska-Stephens, E.; Yang, X.; Slotta, D.J.; Markey, S.P. Composition of the synaptic PSD-95 complex. Mol. Cell. Proteom. 2007, 6, 1749–1760. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, W.; Weng, J.; Zhang, X.; Liu, M.; Zhang, M. Creating conformational entropy by increasing interdomain mobility in ligand binding regulation: A revisit to N-terminal tandem PDZ domains of PSD-95. J. Am. Chem. Soc. 2009, 131, 787–796. [Google Scholar] [CrossRef] [PubMed]
- Kovács, B.; Zajácz-Epresi, N.; Gáspári, Z. Ligand-dependent intra- and interdomain motions in the PDZ12 tandem regulate binding interfaces in postsynaptic density protein-95. FEBS Lett. 2020, 594, 887–902. [Google Scholar] [CrossRef] [Green Version]
- Zeng, M.; Ye, F.; Xu, J.; Zhang, M. PDZ ligand binding-induced conformational coupling of the PDZ–SH3–GK tandems in PSD-95 family MAGUKs. J. Mol. Biol. 2018, 430, 69–86. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; Petit, C.M.; King, D.S.; Lee, A.L. Phosphorylation of a PDZ domain extension modulates binding affinity and interdomain interactions in Postsynaptic Density-95 (PSD-95) protein, a membrane-associated guanylate Kinase (MAGUK). J. Biol. Chem. 2011, 286, 41776–41785. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, J.; Lewis, S.M.; Kuhlman, B.; Lee, A.L. Supertertiary Structure of the MAGUK core from PSD-95. Structure 2013, 21, 402–413. [Google Scholar] [CrossRef] [Green Version]
- Liu, X.; Fuentes, E.J. Emerging themes in PDZ domain signaling. Int. Rev. Cell Mol. Biol. 2019, 343, 129–218. [Google Scholar] [PubMed]
- Gautier, C.; Laursen, L.; Jemth, P.; Gianni, S. Seeking allosteric networks in PDZ domains. Protein Eng. Des. Sel. 2018, 31, 367–373. [Google Scholar] [CrossRef]
- Hultqvist, G.; Haq, S.R.; Punekar, A.S.; Chi, C.N.; Engström, A.; Bach, A.; Strømgaard, K.; Selmer, M.; Gianni, S.; Jemth, P. Energetic Pathway Sampling in a Protein Interaction Domain. Structure 2013, 21, 1193–1202. [Google Scholar] [CrossRef] [Green Version]
- Gianni, S.; Haq, S.R.; Montemiglio, L.C.; Jorgens, M.C.; Engström, A.; Chi, C.N.; Brunori, M.; Jemth, P. Sequence-specific long range networks in PSD-95/Discs large/ZO-1 (PDZ) domains tune their binding selectivity. J. Biol. Chem. 2011, 286, 27167–27175. [Google Scholar] [CrossRef] [Green Version]
- Gerek, Z.N.; Ozkan, S.B. Change in allosteric network affects binding affinities of PDZ domains: Analysis through perturbation response scanning. PLoS Comput. Biol. 2011, 7, e1002154. [Google Scholar] [CrossRef] [PubMed]
- Murciano-Calles, J. The Conformational Plasticity Vista of PDZ Domains. Life 2020, 10, 123. [Google Scholar] [CrossRef]
- Lockless, S.W.; Ranganathan, R. Evolutionarily conserved pathways of energetic connectivity in protein families. Science 1999, 286, 295–299. [Google Scholar] [CrossRef] [Green Version]
- Reynolds, K.A.; McLaughlin, R.N.; Ranganathan, R. Hot spots for allosteric regulation on protein surfaces. Cell 2011, 47, 1564–1575. [Google Scholar] [CrossRef] [Green Version]
- McLaughlin, R.N., Jr.; Poelwijk, F.J.; Raman, A.; Gosal, W.S.; Ranganathan, R. The spatial architecture of protein function and adaptation. Nature 2012, 491, 138–142. [Google Scholar] [CrossRef] [Green Version]
- Salinas, V.H.; Ranagathan, R. Coevolution-based inference of amino acid interactions underlying protein function. eLife 2018, 7, e34300. [Google Scholar] [CrossRef] [PubMed]
- Du, Q.-S.; Wang, C.-H.; Liao, S.-M.; Huang, R.-B. Correlation analysis for protein evolutionary family based on amino acid position mutations and application in PDZ domain. PLoS ONE 2010, 5, e13207. [Google Scholar] [CrossRef] [PubMed]
- Kalescky, R.; Liu, J.; Tao, P. Identifying Key Residues for Protein Allostery through rigid residue scan. J. Phys. Chem. 2015, 119, 1689–1700. [Google Scholar] [CrossRef]
- Kaya, C.; Armutlulu, A.; Ekesan, S.; Haliloglu, T. MCPath: Monte Carlo path generation approach to predict likely allosteric pathways and functional residues. Nucleic Acids Res. 2013, 41, W249–W255. [Google Scholar] [CrossRef]
- 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 2009, 106, 18249–18254. [Google Scholar] [CrossRef] [Green Version]
- Mostarda, S.; Gfeller, D.; Rao, F. Beyond the binding site: The role of the β2-β3 loop and extra-domain structures in PDZ domains. PLoS Comput. Biol. 2012, 8, e1002429. [Google Scholar] [CrossRef] [Green Version]
- Kumawat, A.; Chakrabarty, S. Hidden electrostatic basis of dynamic allostery in a PDZ domain. Proc. Natl. Acad. Sci. USA 2017, 114, E5825–E5834. [Google Scholar] [CrossRef] [Green Version]
- Murciano-Calles, J.; Cobi-Verge, C.; Candel, A.M.; Luque, I.; Martinez, J.C. Post-translational modifications modulate ligand recognition by the third PDZ domain of the MAGUK protein PSD-95. PLoS ONE 2014, 9, e90030. [Google Scholar] [CrossRef]
- Hayatshahi, H.S.; Ahuactzin, E.; Tao, P.; Wang, S.; Liu, J. Probing protein allostery as a residue-specific concept via residue response maps. J. Chem. Inform. Model. 2019, 59, 4691–4705. [Google Scholar] [CrossRef]
- Kumawat, A.; Chakrabarty, S. Protonation-induced dynamic allostery in PDZ domain: Evidence of perturbation-independent universal response network. Phys. Chem. Lett. 2020, 11, 9026–9031. [Google Scholar] [CrossRef]
- Camara-Artigas, A.; Murciano-Calles, J.; Gavira, J.A.; Cobos, E.S.; Martinez, J.C. Novel conformational aspects of the third PDZ domain of the neuronal post-synaptic density-95 protein revealed from two 1.4 Å X-ray structures. J. Struct. Biol. 2010, 170, 565–569. [Google Scholar] [CrossRef] [PubMed]
- Camara-Artigas, A.; Murciano-Calles, J.; Martinez, J.C. Conformational changes in the third PDZ domain of the neuronal postsynaptic density protein 95. Acta Crystallogr. D Struct. Biol. 2019, 75, 381–391. [Google Scholar] [CrossRef]
- Ángyán, A.F.; Gápári, Z. Ensemble-based interpretations of NMR structural data to describe protein internal dynamics. Molecules 2013, 18, 10548–10567. [Google Scholar] [CrossRef] [Green Version]
- Lindorff-Larsen, K.; Best, R.B.; DePristo, M.A.; Dobson, C.M.; Vendruscolo, M. Simultaneous determination of protein structure and dynamics. Nature 2005, 433, 128–132. [Google Scholar] [CrossRef] [PubMed]
- Lange, O.F.; Lakomek, N.-A.; Farés, C.; Schröder, G.F.; Walter, K.F.A.; Becker, S.; Meiler, J.; Grubmüller, H.; Griesinger, C.; de Groot, B.L. Recognition dynamics up to microseconds revealed from an RDC-derivbed ubiquitin ensemble in solution. Science 2008, 320, 1471–1475. [Google Scholar] [CrossRef] [Green Version]
- Sapienza, P.J.; Lee, A.L. Using NMR to study fast dynamics in proteins: Methods and applications. Curr. Opin. Pharmacol. 2010, 10, 723–730. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Best, R.B.; Vendruscolo, M. Determination of protein structures consistent with NMR order parameters. J. Am. Chem. Soc. 2004, 126, 8090–8091. [Google Scholar] [CrossRef] [PubMed]
- Richter, B.; Gsponer, J.; Várnai, P.; Salvatella, X.; Vendrsucolo, M. The MUMO (minimal under-restraining minimal over-restraining) method for the determination of native state ensembles of proteins. J. Biomol. NMR 2007, 37, 117–135. [Google Scholar] [CrossRef]
- Dhulesia, A.; Gsponer, J.; Vendrsucolo, M. Mapping of two networks of residues that exhibit structural and dynamical changes upon binding in a PDZ domain protein. J. Am. Chem. Soc. 2008, 130, 8931–8939. [Google Scholar] [CrossRef]
- Karplus, M.; Kushick, J.N. Method for estimating the configurational entropy of macromolecules. Macromolecules 1981, 14, 325–332. [Google Scholar] [CrossRef]
- Schlitter, J. Estimation of absolute and relative entropies of macro-molecules using the covariance matrix. Chem. Phys. Lett. 1993, 215, 617–621. [Google Scholar] [CrossRef]
- Tochio, H.; Zhang, Q.; Mandal, P.; Li, M.; Zhang, M. Solution structure of the extended neuronal nitric oxide synthase PDZ domain complexed with an associated peptide. Nat. Struct. Mol. Biol. 1999, 6, 417–421. [Google Scholar]
- Czajlik, A.; Kovács, B.; Permi, P.; Gáspári, Z. Fine-tuning the extent and dynamics of binding cleft opening as a potential general regulatory mechanism in parvulin-type peptidyl prolyl isomerases. Sci. Rep. 2017, 7, 44504. [Google Scholar] [CrossRef] [Green Version]
- Fuentes, E.J.; Der, C.J.; Lee, A.L. Ligand-dependent dynamics and intramolecular signaling in a PDZ domain. J. Mol. Biol. 2004, 335, 1105–1115. [Google Scholar] [CrossRef]
- Motlagh, H.N.; Wrabl, J.O.; Li, J.; Hilsert, V.J. The ensemble nature of allostery. Nature 2014, 508, 331–339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Doyle, D.A.; Lee, A.; Lewis, J.; Kim, E.; Sheng, M.; McKinnon, R. Crystal structures of a complexed and peptide-free membrane protein–binding domain: Molecular basis of peptide recognition by PDZ. Structure 1996, 85, 1067–1076. [Google Scholar] [CrossRef] [Green Version]
- Van Der Spoel, D.; Lindahl, E.; Hess, B.; Groenhof, G.; Mark, A.E.; Berendsen, H.J.C. GROMACS: Fast, flexible and free. J. Comput. Chem. 2005, 26, 1701–1718. [Google Scholar] [CrossRef]
- Fizil, Á.; Gáspári, Z.; Terézia, B.; Marx, F.; Batta, G. “Invisible” conformers of an antifungal disulfide protein revealed by constrained cold and heat unfolding, CEST-NMR experiments, and molecular dynamics calculations. Chem. Eur. J. 2015, 21, 5136–5144. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dudola, D.; Kovács, B.; Gáspári, Z. CoNSEnsX+ webserver for the analysis of protein structural ensembles reflecting experimentally determined internal dynamics. J. Chem. Inform. Model. 2017, 57, 1728–1734. [Google Scholar] [CrossRef]
- Lindorff-Larsen, K.; Piana, S.; Palmo, K.; Maragakis, P.; Klepeis, J.L.; Dorr, R.O.; Shaw, D.E. Improved side-chain torsion potentials for the AMBER ff99SB protein force field. Proteins 2010, 78, 1950–1958. [Google Scholar] [CrossRef] [Green Version]
- Bakan, A.; Meierles, L.M.; Bahar, I. ProDy: Protein dynamics inferred from theory and experiments. Bioinformatics 2011, 27, 1575–1577. [Google Scholar] [CrossRef] [Green Version]
- Olechnovic, K.; Venclovas, C. Voronota: A fast and reliable tool for computing the vertices of the Voronoi diagram of atomic balls. J. Comput. Chem. 2014, 35, 672–681. [Google Scholar] [CrossRef]
- Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 2003, 13, 2498–2504. [Google Scholar] [CrossRef] [PubMed]
- Koradi, R.; Billeter, M.; Wüthrich, K. MOLMOL: A program for display and analysis of macromolecular structures. J. Mol. Graph. 1996, 14, 29–32. [Google Scholar] [CrossRef]
- Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera—A visualization system for exploratory research and analysis. J. Comput. Chem. 2004, 25, 1605–1612. [Google Scholar] [CrossRef] [Green Version]
- Lupyan, D.; Leo-Macias, A.; Ortiz, A.R. A new progressive-iterative algorithm for multiple structure alignment. Bioinformatics 2005, 21, 3255–3263. [Google Scholar] [CrossRef]
Ensemble | Backbone S | Side-Chain S |
---|---|---|
Free full-length (ff) | 0.92 | 0.95 |
Free 7CT (fd) | 0.87 | 0.96 |
Complex full-length (cf) | 0.95 | 0.97 |
Complex 7CT (cd) | 0.83 | 0.95 |
Complex | Complex | Free | Free | ||||
---|---|---|---|---|---|---|---|
Ensemble | All4 | 7CT | Complex | 7CT | Full | 7CT | Full |
Open | 53% | 35% | 10% | 2% | 18% | 69% | 97% |
Narrow | 54% | 30% | 50% | 31% | 69% | 30% | 87% |
Open-Narrow co-occurrence | 0.56 | 0.51 | 0.54 | 0.68 | 0.61 | 0.67 | 0.85 |
PC# | Description | PSD95 PDZ Domains | PSD-95 PDZ3 Only |
---|---|---|---|
1 | 4-2 loop dominant | 1 | - |
2 | narrow-wide like | 2 | - |
3 | 2 seesaw | - | - |
4 | opening-closing | 3 | 1 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Dudola, D.; Hinsenkamp, A.; Gáspári, Z. Ensemble-Based Analysis of the Dynamic Allostery in the PSD-95 PDZ3 Domain in Relation to the General Variability of PDZ Structures. Int. J. Mol. Sci. 2020, 21, 8348. https://doi.org/10.3390/ijms21218348
Dudola D, Hinsenkamp A, Gáspári Z. Ensemble-Based Analysis of the Dynamic Allostery in the PSD-95 PDZ3 Domain in Relation to the General Variability of PDZ Structures. International Journal of Molecular Sciences. 2020; 21(21):8348. https://doi.org/10.3390/ijms21218348
Chicago/Turabian StyleDudola, Dániel, Anett Hinsenkamp, and Zoltán Gáspári. 2020. "Ensemble-Based Analysis of the Dynamic Allostery in the PSD-95 PDZ3 Domain in Relation to the General Variability of PDZ Structures" International Journal of Molecular Sciences 21, no. 21: 8348. https://doi.org/10.3390/ijms21218348