In Silico Study of the Mechanism of Binding of the N-Terminal Region of α Synuclein to Synaptic-Like Membranes
Abstract
:1. Introduction
2. Materials and Methods
2.1. Simulation Setup
2.2. CG Implementation
3. Results
3.1. Conformational Dependency in the Membrane Binding of N-Terminal Region αS
3.2. Sequence Dependencies in the Membrane Affinity of αS1–30
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Jakes, R.; Spillantini, M.G.; Goedert, M. Identification of two distinct synucleins from human brain. FEBS Lett. 1994, 345, 27–32. [Google Scholar] [CrossRef] [Green Version]
- Clayton, D.F.; George, J.M. The synucleins: A family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci. 1998, 21, 249–254. [Google Scholar] [CrossRef]
- Lashuel, H.A.; Overk, C.R.; Oueslati, A.; Masliah, E. The many faces of α-synuclein: From structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 2013, 14, 38–48. [Google Scholar] [CrossRef] [Green Version]
- Jucker, M.; Walker, L.C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 2013, 501, 45–51. [Google Scholar] [CrossRef] [Green Version]
- Bosco, D.A.; Fowler, D.M.; Zhang, Q.; Nieva, J.; Powers, E.T.; Wentworth, P.; Lerner, R.A.; Kelly, J.W. Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate α-synuclein fibrilization. Nat. Chem. Biol. 2006, 2, 249–253. [Google Scholar] [CrossRef] [PubMed]
- Luk, K.C.; Kehm, V.; Carroll, J.; Zhang, B.; Brien, P.O.; Trojanowski, J.Q.; Lee, V.M. Pathological a-synuclein transmission initiates parkinson-like neurodegeneration in nontransgenic mice. Science 2012, 338, 949–954. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chiti, F.; Dobson, C.M. Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade. Annu. Rev. Biochem. 2017, 86, 27–68. [Google Scholar] [CrossRef] [PubMed]
- Uversky, V.; Eliezer, D. Biophysics of parkinsons disease: Structure and aggregation of α-synuclein. Curr. Protein Pept. Sci. 2009, 10, 483–499. [Google Scholar] [CrossRef] [PubMed]
- Krüger, R.; Kuhn, W.; Müller, T.; Woitalla, D.; Graeber, M.; Kösel, S.; Przuntek, H.; Epplen, J.T.; Schöls, L.; Riess, O. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat. Genet. 1998, 18, 106–108. [Google Scholar] [CrossRef] [PubMed]
- Singleton, A.B.; Farrer, M.; Johnson, J.; Singleton, A.; Hague, S.; Kachergus, J.; Hulihan, M.; Peuralinna, T.; Dutra, A.; Nussbaum, R.; et al. α-Synuclein locus triplication causes Parkinson’s disease. Science 2003, 302, 841. [Google Scholar] [CrossRef] [Green Version]
- Zarranz, J.J.; Alegre, J.; Gómez-Esteban, J.C.; Lezcano, E.; Ros, R.; Ampuero, I.; Vidal, L.; Hoenicka, J.; Rodriguez, O.; Atarés, B.; et al. The new mutation, E46K, of α-Synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 2004, 55, 164–173. [Google Scholar] [CrossRef] [PubMed]
- Spillantini, M.G.; Crowther, R.A.; Jakes, R.; Cairns, N.J.; Lantos, P.L.; Goedert, M. Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett. 1998, 251, 205–208. [Google Scholar] [CrossRef]
- Galvin, J.E.; Uryu, K.; Lee, V.M.Y.; Trojanowski, J.Q. Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains α-, β-, and γ-synuclein. Proc. Natl. Acad. Sci. USA 1999, 96, 13450–13455. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Burré, J. The synaptic function of α-synuclein. J. Parkinsons. Dis. 2015, 5, 699–713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Burré, J.; Sharma, M.; Südhof, T.C. α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc. Natl. Acad. Sci. USA 2014, 111, E4274–E4283. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Burré, J.; Sharma, M.; Tsetsenis, T.; Buchman, V.; Etherton, M.R.; Südhof, T.C. A-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 2010, 1663, 1663–1668. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gitler, A.D.; Bevis, B.J.; Shorter, J.; Strathearn, K.E.; Hamamichi, S.; Su, L.J.; Caldwell, K.A.; Caldwell, G.A.; Rochet, J.-C.; McCaffery, J.M.; et al. The Parkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc. Natl. Acad. Sci. USA 2008, 105, 145–150. [Google Scholar] [CrossRef] [Green Version]
- Diao, J.; Burré, J.; Vivona, S.; Cipriano, D.J.; Sharma, M.; Kyoung, M.; Südhof, T.C.; Brunger, A.T. Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. Elife 2013, 2013, 1–17. [Google Scholar] [CrossRef]
- Bodner, C.R.; Dobson, C.M.; Bax, A. Multiple tight phospholipid-binding modes of α-Synuclein revealed by solution NMR spectroscopy. J. Mol. Biol. 2009, 390, 775–790. [Google Scholar] [CrossRef] [Green Version]
- Fusco, G.; Pape, T.; Stephens, A.D.; Mahou, P.; Costa, A.R.; Kaminski, C.F.; Kaminski Schierle, G.S.; Vendruscolo, M.; Veglia, G.; Dobson, C.M.; et al. Structural basis of synaptic vesicle assembly promoted by α-synuclein. Nat. Commun. 2016, 7, 1–11. [Google Scholar] [CrossRef] [Green Version]
- Nemani, V.M.; Lu, W.; Berge, V.; Nakamura, K.; Onoa, B.; Lee, M.K.; Chaudhry, F.A.; Nicoll, R.A.; Edwards, R.H. Increased expression of α-Synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 2010, 65, 66–79. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Auluck, P.K.; Caraveo, G.; Lindquist, S. α-Synuclein: Membrane interactions and toxicity in Parkinson’s disease. Annu. Rev. Cell Dev. Biol. 2010, 26, 211–233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cooper, A.A. α-Synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 2006, 313, 324–328. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Menges, S.; Minakaki, G.; Schaefer, P.M.; Meixner, H.; Prots, I.; Schlötzer-Schrehardt, U.; Friedland, K.; Winner, B.; Outeiro, T.F.; Winklhofer, K.F.; et al. Alpha-synuclein prevents the formation of spherical mitochondria and apoptosis under oxidative stress. Sci. Rep. 2017, 7, 1–25. [Google Scholar] [CrossRef] [Green Version]
- Ludtmann, M.H.R.; Angelova, P.R.; Ninkina, N.N.; Gandhi, S.; Buchman, V.L.; Abramov, A.Y. Monomeric alpha-synuclein exerts a physiological role on brain ATP synthase. J. Neurosci. 2016, 36, 10510–10521. [Google Scholar] [CrossRef]
- Lee, H.J.; Choi, C.; Lee, S.J. Membrane-bound α-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. J. Biol. Chem. 2002, 277, 671–678. [Google Scholar] [CrossRef] [Green Version]
- Galvagnion, C.; Buell, A.K.; Meisl, G.; Michaels, T.C.T.; Vendruscolo, M.; Knowles, T.P.J.; Dobson, C.M. Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. Nat. Chem. Biol. 2015, 11, 229–234. [Google Scholar] [CrossRef] [Green Version]
- Perrin, R.J.; Woods, W.S.; Clayton, D.F.; George, J.M. Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J. Biol. Chem. 2001, 276, 41958–41962. [Google Scholar] [CrossRef] [Green Version]
- Galvagnion, C.; Maltsev, A.; Meisl, G.; Müller, M.B.D.; Challa, P.K.; Kirkegaard, J.B.; Cohen, S.I.A.; Cascella, R.; Chen, S.W.; Limboker, R.; et al. Correction for Perni et al., A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity. Proc. Natl. Acad. Sci. USA 2017, 114, E2543. [Google Scholar] [CrossRef] [Green Version]
- Chen, S.W.; Drakulic, S.; Deas, E.; Ouberai, M.; Aprile, F.A.; Arranz, R.; Ness, S.; Roodveldt, C.; Guilliams, T.; De-Genst, E.J.; et al. Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation. Proc. Natl. Acad. Sci. USA 2015, 112, E1994–E2003. [Google Scholar] [CrossRef] [Green Version]
- Theillet, F.X.; Binolfi, A.; Bekei, B.; Martorana, A.; Rose, H.M.; Stuiver, M.; Verzini, S.; Lorenz, D.; Van Rossum, M.; Goldfarb, D.; et al. Structural disorder of monomeric α-synuclein persists in mammalian cells. Nature 2016, 530, 45–50. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Maltsev, A.S.; Ying, J.; Bax, A. Impact of N-terminal acetylation of α-synuclein on its random coil and lipid binding properties. Biochemistry 2012, 51, 5004–5013. [Google Scholar] [CrossRef] [PubMed]
- Fusco, G.; Sanz-Hernandez, M.; Ruggeri, F.S.; Vendruscolo, M.; Dobson, C.M.; De Simone, A. Molecular determinants of the interaction of EGCG with ordered and disordered proteins. Biopolymers 2018, 109, 1–9. [Google Scholar] [CrossRef] [PubMed]
- Ulmer, T.S.; Bax, A.; Cole, N.B.; Nussbaum, R.L. Structure and dynamics of micelle-bound human α-synuclein. J. Biol. Chem. 2005, 280, 9595–9603. [Google Scholar] [CrossRef] [Green Version]
- Eliezer, D.; Kutluay, E.; Bussell, R.; Browne, G. Conformational properties of α-synuclein in its free and lipid-associated states. J. Mol. Biol. 2001, 307, 1061–1073. [Google Scholar] [CrossRef]
- Fusco, G.; Sanz-Hernandez, M.; De Simone, A. Order and disorder in the physiological membrane binding of α-synuclein. Curr. Opin. Struct. Biol. 2018, 48, 49–57. [Google Scholar] [CrossRef]
- Trexler, A.J.; Rhoades, E. α-Synuclein binds large unilamellar vesicles as an extended helix. Biochemistry 2009, 48, 2304–2306. [Google Scholar] [CrossRef] [Green Version]
- Jao, C.C.; Hegde, B.G.; Chen, J.; Haworth, I.S.; Langen, R. Structure of membrane-bound alpha-synuclein from site-directed spin labeling and computational refinement. Proc. Natl. Acad. Sci. USA 2008, 105, 19666–19671. [Google Scholar] [CrossRef] [Green Version]
- Burré, J.; Sharma, M.; Südhof, T.C. Definition of a molecular pathway mediating α-synuclein neurotoxicity. J. Neurosci. 2015, 35, 5221–5232. [Google Scholar] [CrossRef] [Green Version]
- Fusco, G.; De Simone, A.; Gopinath, T.; Vostrikov, V.; Vendruscolo, M.; Dobson, C.M.; Veglia, G. Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour. Nat. Commun. 2014, 5, 1–8. [Google Scholar] [CrossRef]
- Lautenschläger, J.; Stephens, A.D.; Fusco, G.; Ströhl, F.; Curry, N.; Zacharopoulou, M.; Michel, C.H.; Laine, R.; Nespovitaya, N.; Fantham, M.; et al. C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction. Nat. Commun. 2018, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bond, P.J.; Holyoake, J.; Ivetac, A.; Khalid, S.; Sansom, M.S.P. Coarse-grained molecular dynamics simulations of membrane proteins and peptides. J. Struct. Biol. 2007, 157, 593–605. [Google Scholar] [CrossRef] [PubMed]
- Abraham, M.J.; Murtola, T.; Schulz, R.; Páll, S.; Smith, J.C.; Hess, B.; Lindahl, E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 2015, 1–2, 19–25. [Google Scholar] [CrossRef] [Green Version]
- Bruininks, B.M.H.; Souza, P.C.T.; Marrink, S.J. A practical view of the martini force field. Methods Mol. Biol. 2019, 2022, 105–127. [Google Scholar] [CrossRef] [PubMed]
- Wassenaar, T.A.; Ingólfsson, H.I.; Böckmann, R.A.; Tieleman, D.P.; Marrink, S.J. Computational lipidomics with insane: A versatile tool for generating custom membranes for molecular simulations. J. Chem. Theory Comput. 2015, 11, 2144–2155. [Google Scholar] [CrossRef] [PubMed]
- Bussi, G.; Donadio, D.; Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 2007, 126, 014101. [Google Scholar] [CrossRef] [Green Version]
- Berendsen, H.J.C.; Postma, J.P.M.; Van Gunsteren, W.F.; Dinola, A.; Haak, J.R. Molecular dynamics with coupling to an external bath. J. Chem. Phys. 1984, 81, 3684–3690. [Google Scholar] [CrossRef] [Green Version]
- Parrinello, M.; Rahman, A. Polymorphic transitions in single crystals: A new molecular dynamics method. J. Appl. Phys. 1981, 52, 7182–7190. [Google Scholar] [CrossRef]
- Hess, B.; Bekker, H.; Berendsen, H.J.C.; Fraaije, J.G.E.M. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem. 1997, 18, 1463–1472. [Google Scholar] [CrossRef]
- Fusco, G.; De Simone, A.; Arosio, P.; Vendruscolo, M.; Veglia, G.; Dobson, C.M. Structural ensembles of membrane-bound α-Synuclein reveal the molecular determinants of synaptic vesicle affinity. Sci. Rep. 2016, 6, 1–9. [Google Scholar] [CrossRef] [Green Version]
- Vamvaca, K.; Volles, M.J.; Lansbury, P.T. The first N-terminal amino acids of α-Synuclein are essential for α-Helical structure formation in vitro and membrane binding in yeast. J. Mol. Biol. 2009, 389, 413–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Newberry, R.W.; Leong, J.T.; Chow, E.D.; Kampmann, M.; DeGrado, W.F. Deep mutational scanning reveals the structural basis for α-synuclein activity. Nat. Chem. Biol. 2020. [Google Scholar] [CrossRef] [PubMed]
- Snead, D.; Eliezer, D. Alpha-Synuclein function and dysfunction on cellular membranes. Exp. Neurobiol. 2014, 23, 292–313. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhu, M.; Fink, A.L. Lipid binding inhibits α-synuclein fibril formation. J. Biol. Chem. 2003, 278, 16873–16877. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fusco, G.; Chen, S.W.; Williamson, P.T.F.; Cascella, R.; Perni, M.; Jarvis, J.A.; Cecchi, C.; Vendruscolo, M.; Chiti, F.; Cremades, N.; et al. Structural basis of membrane disruption and cellular toxicity by a-synuclein oligomers. Science 2017, 358, 1440–1443. [Google Scholar] [CrossRef] [Green Version]
Name | Protein Sequence | Nr of Waters |
---|---|---|
WT αS1–30 | MDVFMKGLSKAKEGVVAAAEKTKQGVAEAA | 8954 |
Del 2 αS1–30 | MVFMKGLSKAKEGVVAAAEKTKQGVAEAA | 8949 |
Del 2–3 αS1–30 | MFMKGLSKAKEGVVAAAEKTKQGVAEAA | 8947 |
Del 2–4 αS1–30 | MMKGLSKAKEGVVAAAEKTKQGVAEAA | 8957 |
Del 2–5 αS1–30 | MKGLSKAKEGVVAAAEKTKQGVAEAA | 8964 |
Del 2–7 αS1–30 | MLSKAKEGVVAAAEKTKQGVAEAA | 8963 |
Del 2–11 αS1–30 | MKEGVVAAAEKTKQGVAEAA | 8981 |
CT αS111–140 | GILEDMPVDPDNEAYEMPSEEGYQDYEPEA | 8916 |
F4A αS1–30 | MDVAMKGLSKAKEGVVAAAEKTKQGVAEAA | 8696 |
σ 114° αS1–30 | MDVFMKGLSKAKEGVVAAAEKTKQGVAEAA | 8686 |
© 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
Navarro-Paya, C.; Sanz-Hernandez, M.; De Simone, A. In Silico Study of the Mechanism of Binding of the N-Terminal Region of α Synuclein to Synaptic-Like Membranes. Life 2020, 10, 98. https://doi.org/10.3390/life10060098
Navarro-Paya C, Sanz-Hernandez M, De Simone A. In Silico Study of the Mechanism of Binding of the N-Terminal Region of α Synuclein to Synaptic-Like Membranes. Life. 2020; 10(6):98. https://doi.org/10.3390/life10060098
Chicago/Turabian StyleNavarro-Paya, Carlos, Maximo Sanz-Hernandez, and Alfonso De Simone. 2020. "In Silico Study of the Mechanism of Binding of the N-Terminal Region of α Synuclein to Synaptic-Like Membranes" Life 10, no. 6: 98. https://doi.org/10.3390/life10060098