Structural disorder of monomeric α-synuclein persists in mammalian cells

Nature

Volumn 530, Issue 7588, 2016, Pages 45-50

  Theillet, Francois Xavier ^a,c   Binolfi, Andres ^a,d   Bekei, Beata ^a   Martorana, Andrea ^b   Rose, Honor May ^a   Stuiver, Marchel ^a   Verzini, Silvia ^a   Lorenz, Dorothea ^a   Van Rossum, Marleen ^a   Goldfarb, Daniella ^b   Selenko, Philipp ^a  

^a LEIBNIZ INSTITUT FÜR MOLEKULARE PHARMAKOLOGIE   (Germany)

^b WEIZMANN INSTITUTE OF SCIENCE   (Israel)

^c INSTITUTE FOR INTEGRATIVE BIOLOGY OF THE CELL I2BC   (France)

^d Universidad Nacional de Rosario   (Argentina)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SYNUCLEIN;

CELLS AND CELL COMPONENTS; CYTOPLASM; DISEASE; ELECTRON SPIN RESONANCE; MAMMAL; NUCLEAR MAGNETIC RESONANCE; PROTEIN;

ARTICLE; ELECTRON SPIN RESONANCE; HUMAN; MAMMAL CELL; NERVE CELL; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OLIGOMERIZATION; PRIORITY JOURNAL; PROTEIN ACETYLATION; PROTEIN AGGREGATION; PROTEIN CONFORMATION; PROTEIN STRUCTURE; ACETYLATION; CELL LINE; CHEMISTRY; CYTOLOGY; CYTOPLASM; HELA CELL LINE; INTRACELLULAR SPACE; METABOLISM; NUCLEAR MAGNETIC RESONANCE;

MAMMALIA;

ACETYLATION; ALPHA-SYNUCLEIN; CELL LINE; CYTOPLASM; ELECTRON SPIN RESONANCE SPECTROSCOPY; HELA CELLS; HUMANS; INTRACELLULAR SPACE; NEURONS; NUCLEAR MAGNETIC RESONANCE, BIOMOLECULAR; PROTEIN CONFORMATION;

EID: 84955515311     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature16531     Document Type: Article

References (36)

1. Theillet, F. X. et al. Physicochemical properties of cells and their effects on intrinsically disordered proteins (IDPs). Chem. Rev. 114, 6661-6714 (2014).
2. Goedert, M., Spillantini, M. G., Del Tredici, K. & Braak, H. 100 years of Lewy pathology. Nature Rev. Neurol. 9, 13-24 (2013).
3. Iwai, A. et al. The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron 14, 467-475 (1995).
4. Lashuel, H. A., Overk, C. R., Oueslati, A. & Masliah, E. The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nature Rev. Neurosci. 14, 38-48 (2013).
5. Dettmer, U., Selkoe, D. & Bartels, T. New insights into cellular α-synuclein homeostasis in health and disease. Curr. Opin. Neurobiol. 36, 15-22 (2015).
6. Bartels, T., Choi, J. G. & Selkoe, D. J. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477, 107-110 (2011).
7. Wang, W. et al. A soluble α-synuclein construct forms a dynamic tetramer. Proc. Natl Acad. Sci. USA 108, 17797-17802 (2011).
8. Binolfi, A., Theillet, F. X. & Selenko, P. Bacterial in-cell NMR of human alpha-synuclein: a disordered monomer by nature? Biochem. Soc. Trans. 40, 950-954 (2012).
9. Burré, J. et al. Properties of native brain α-synuclein. Nature 498, E4-E6 (2013).
10. Fauvet, B. et al. Characterization of semisynthetic and naturally N-alpha-acetylated α-synuclein in vitro and in intact cells: implications for aggregation and cellular properties of alpha-synuclein. J. Biol. Chem. 287, 28243-28262 (2012).
11. Fauvet, B. et al. α-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J. Biol. Chem. 287, 15345-15364 (2012).
12. Dettmer, U., Newman, A. J., Luth, E. S., Bartels, T. & Selkoe, D. In vivo cross-linking reveals principally oligomeric forms of α-synuclein and β-synuclein in neurons and non-neural cells. J. Biol. Chem. 288, 6371-6385 (2013).
13. Dettmer, U. et al. Parkinson-causing alpha-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nature Commun. 6, 7314 (2015).
14. Luth, E. S., Bartels, T., Dettmer, U., Kim, N. C. & Selkoe, D. J. Purification of α-synuclein from human brain reveals an instability of endogenous multimers as the protein approaches purity. Biochemistry 54, 279-292 (2015).
15. Selkoe, D. et al. Defining the native state of α-synuclein. Neurodegener. Dis. 13, 114-117 (2014).
16. Uversky, V. N. Intrinsically disordered proteins and their (disordered) proteomes in neurodegenerative disorders. Front. Aging Neurosci. 7, 18 (2015).
17. Paris, I. et al. The catecholaminergic RCSN-3 cell line: a model to study dopamine metabolism. Neurotox. Res. 13, 221-230 (2008).
18. Wilhelm, B. G. et al. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science 344, 1023-1028 (2014).
19. Okochi, M. et al. Constitutive phosphorylation of the Parkinson's disease associated α-synuclein. J. Biol. Chem. 275, 390-397 (2000).
20. Starheim, K. K., Gevaert, K. & Arnesen, T. Protein N-terminal acetyltransferases: when the start matters. Trends Biochem. Sci. 37, 152-161 (2012).
21. Kang, L. et al. N-terminal acetylation of alpha-synuclein induces increased transient helical propensity and decreased aggregation rates in the intrinsically disordered monomer. Protein Sci. 21, 911-917 (2012).
22. Maltsev, A. S., Ying, J. F. & Bax, A. Impact of N-terminal acetylation of α-synuclein on its random coil and lipid binding properties. Biochemistry 51, 5004-5013 (2012).
23. Dikiy, I. & Eliezer, D. N-terminal acetylation stabilizes N-terminal helicity in lipid- and micelle-bound alpha-synuclein and increases its affinity for physiological membranes. J. Biol. Chem. 289, 3652-3665 (2014).
24. Li, C. et al. Differential dynamical effects of macromolecular crowding on an intrinsically disordered protein and a globular protein: Implications for in-cell NMR spectroscopy. J. Am. Chem. Soc. 130, 6310-6311 (2008).
25. Fusco, G. et al. Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour. Nature Commun. 5, 3827 (2014).
26. + spin labelling. J. Am. Chem. Soc. 136, 13458-13465 (2014).
27. Bertoncini, C. W. et al. Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein. Proc. Natl Acad. Sci. USA 102, 1430-1435 (2005).
28. Dedmon, M. M., Lindorff-Larsen, K., Christodoulou, J., Vendruscolo, M. &Dobson, C. M. Mapping long-range interactions in α-synuclein using spin-label NMR and ensemble molecular dynamics simulations. J. Am. Chem. Soc. 127, 476-477 (2005).
29. Wu, K. P. & Baum, J. Detection of transient interchain interactions in the intrinsically disordered protein α-synuclein by NMR paramagnetic relaxation enhancement. J. Am. Chem. Soc. 132, 5546-5547 (2010).
30. Kostka, M. et al. Single particle characterization of iron-induced pore-forming α-synuclein oligomers. J. Biol. Chem. 283, 10992-11003 (2008).
31. Danielsson, J. et al. Thermodynamics of protein destabilization in live cells. Proc. Natl Acad. Sci. USA 112, 12402-12407 (2015).
32. Monteith, W. B., Cohen, R. D., Smith, A. E., Guzman-Cisneros, E. & Pielak, G. J. Quinary structure modulates protein stability in cells. Proc. Natl Acad. Sci. USA 112, 1739-1742 (2015).
33. Cremades, N. et al. Direct observation of the interconversion of normal and toxic forms of α-synuclein. Cell 149, 1048-1059 (2012).
34. Galvagnion, C. et al. Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. Nature Chem. Biol. 11, 229-234 (2015).
35. Lamberto, G. R. et al. Structural and mechanistic basis behind the inhibitory interaction of PcTS on α-synuclein amyloid fibril formation. Proc. Natl Acad. Sci. USA 106, 21057-21062 (2009).
36. Ulmer, T. S. & Bax, A. Comparison of structure and dynamics of micellebound human α-synuclein and Parkinson disease variants. J. Biol. Chem. 280, 43179-43187 (2005).