Article

You have full text access to this OnlineOpen article

Charge neutralization and collapse of the C-terminal tail of alpha-synuclein at low pH

  1. Sebastian McClendon,
  2. Carla C. Rospigliosi,
  3. David Eliezer*

Article first published online: 29 APR 2009

DOI: 10.1002/pro.149

Issue

Protein Science

Protein Science

Volume 18, Issue 7, pages 1531–1540, July 2009

Additional Information

How to Cite

McClendon, S., Rospigliosi, C. C. and Eliezer, D. (2009), Charge neutralization and collapse of the C-terminal tail of alpha-synuclein at low pH. Protein Science, 18: 1531–1540. doi: 10.1002/pro.149

Author Information

  1. Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065

*Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065

Publication History

  1. Issue published online: 23 JUN 2009
  2. Article first published online: 29 APR 2009
  3. Accepted manuscript online: 29 APR 2009 12:00AM EST
  4. Manuscript Accepted: 13 APR 2009
  5. Manuscript Revised: 9 APR 2009
  6. Manuscript Received: 20 FEB 2009

Funded by

  • NIH. Grant Numbers: F32 NS058137 (SM), R01 AG019391 (DE), R01 AG025440 (DE), P41 GM66354 (NYSBC)
  • Irma T. Hirschl Foundation (DE)
  • Keck Foundation, New York State
  • NYC Economic Development Corporation (NYSBC)
  • Herbert and Ann Siegel
  • New York State Office of Science, Technology and Academic Research
  • NIH, USA
  • Keck Foundation, New York

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

View Full Article (HTML) Get PDF (584K)

References

  • 1
    Lang AE, Lozano AM ( 1998) Parkinson's disease. Second of two parts. N Engl J Med 339: 1130–1143.
  • 2
    Schrag A, Ben-Shlomo Y, Quinn NP ( 2000) Cross sectional prevalence survey of idiopathic Parkinson's disease and Parkinsonism in London. BMJ 321: 21–22.
  • 3
    Dauer W, Przedborski S ( 2003) Parkinson's disease: mechanisms and models. Neuron 39: 889–909.
  • 4
    Goedert M ( 2001) α-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2: 492–501.
  • 5
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M ( 1997) α-Synuclein in Lewy bodies. Nature 388: 839–840.
  • 6
    Conway KA, Harper JD, Lansbury PT, Jr ( 2000) Fibrils formed in vitro from α-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid. Biochemistry 39: 2552–2563.
  • 7
    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL ( 1997) Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276: 2045–2047.
  • 8
    Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O ( 1998) Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat Genet 18: 106–108.
  • 9
    Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez Tortosa E, del Ser T, Munoz DG, de Yebenes JG ( 2004) The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55: 164–173.
    Direct Link:
  • 10
    Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, Pollak P, Agid Y, Durr A, Brice A ( 2004) Causal relation between α-synuclein gene duplication and familial Parkinson's disease. Lancet 364: 1169–1171.
  • 11
    Ahn TB, Kim SY, Kim JY, Park SS, Lee DS, Min HJ, Kim YK, Kim SE, Kim JM, Kim, HJ, Cho J, Jeon BS ( 2008) α-Synuclein gene duplication is present in sporadic Parkinson disease. Neurology 70: 43–49.
  • 12
    Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K ( 2003) α-Synuclein locus triplication causes Parkinson's disease. Science 302: 841.
  • 13
    Cowan R, Whittaker RG ( 1990) Hydrophobicity indices for amino acid residues as determined by high-performance liquid chromatography. Pept Res 3: 75–80.
  • 14
    Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T ( 1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90: 11282–11286.
  • 15
    Der-Sarkissian A, Jao CC, Chen J, Langen, R ( 2003) Structural organization of α-synuclein fibrils studied by site-directed spin labeling. J Biol Chem 278: 37530–37535.
  • 16
    Del Mar C, Greenbaum EA, Mayne L, Englander SW, Woods VL, Jr ( 2005) Structure and properties of α-synuclein and other amyloids determined at the amino acid level. Proc Natl Acad Sci USA 102: 15477–15482.
  • 17
    Heise H, Hoyer W, Becker S, Andronesi OC, Riedel D, Baldus M ( 2005) Molecular-level secondary structure, polymorphism, and dynamics of full-length α-synuclein fibrils studied by solid-state NMR. Proc Natl Acad Sci USA 102: 15871–15876.
  • 18
    Vilar M, Chou HT, Luhrs T, Maji SK, Riek-Loher D, Verel R, Manning G, Stahlberg H, Riek R ( 2008) The fold of α-synuclein fibrils. Proc Natl Acad Sci USA 105: 8637–8642.
  • 19
    Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT, Jr ( 2000) Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA 97: 571–576.
  • 20
    Kaylor J, Bodner N, Edridge S, Yamin G, Hong DP, Fink AL ( 2005) Characterization of oligomeric intermediates in α-synuclein fibrillation: FRET studies of Y125W/Y133F/Y136F α-synuclein. J Mol Biol 353: 357–372.
  • 21
    Conway KA, Harper JD, Lansbury PT ( 1998) Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease. Nat Med 4: 1318–1320.
  • 22
    Narhi L, Wood SJ, Steavenson S, Jiang Y, Wu GM, Anafi D, Kaufman SA, Martin F, Sitney K, Denis P, Louis JC, Wypych J, Biere AL, Citron M ( 1999) Both familial Parkinson's disease mutations accelerate α-synuclein aggregation. J Biol Chem 274: 9843–9846.
  • 23
    Giasson BI, Uryu K, Trojanowski JQ, Lee VM ( 1999) Mutant and wild type human α-synucleins assemble into elongated filaments with distinct morphologies in vitro. J Biol Chem 274: 7619–7622.
  • 24
    Choi W, Zibaee S, Jakes R, Serpell LC, Davletov B, Crowther RA, Goedert M ( 2004) Mutation E46K increases phospholipid binding and assembly into filaments of human α-synuclein. FEBS Lett 576: 363–368.
  • 25
    Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW, Axelsen PH, Giasson BI ( 2005) The E46K mutation in α-synuclein increases amyloid fibril formation. J Biol Chem 280: 7800–7807.
  • 26
    Conway KA, Lee SJ, Rochet JC, Ding TT, Harper JD, Williamson RE, Lansbury PT, Jr ( 2000) Accelerated oligomerization by Parkinson's disease linked α-synuclein mutants. Ann N Y Acad Sci 920: 42–45.
    Direct Link:
  • 27
    Li J, Uversky VN, Fink AL ( 2001) Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human α-synuclein. Biochemistry 40: 11604–11613.
  • 28
    Wood SJ, Wypych J, Steavenson S, Louis JC, Citron M, Biere AL ( 1999) α-Synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease. J Biol Chem 274: 19509–11952.
  • 29
    Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT, Jr ( 1996) NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry 35: 13709–13715.
  • 30
    Eliezer D, Kutluay E, Bussell R, Jr, Browne G ( 2001) Conformational properties of α-synuclein in its free and lipid-associated states. J Mol Biol 307: 1061–1073.
  • 31
    Dedmon MM, Lindorff-Larsen K, Christodoulou J, Vendruscolo M, Dobson CM ( 2005) Mapping long-range interactions in α-synuclein using spin-label NMR and ensemble molecular dynamics simulations. J Am Chem Soc 127: 476–477.
  • 32
    Bertoncini CW, Jung YS, Fernandez CO, Hoyer W, Griesinger C, Jovin TM, Zweckstetter M ( 2005) Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein. Proc Natl Acad Sci USA 102: 1430–1435.
  • 33
    Uversky VN, Li J, Fink AL ( 2001) Evidence for a partially folded intermediate in α-synuclein fibril formation. J Biol Chem 276: 10737–10744.
  • 34
    Morris AM, Finke RG ( 2009) α-Synuclein aggregation variable temperature and variable pH kinetic data: a re-analysis using the Finke-Watzky 2-step model of nucleation and autocatalytic growth. Biophys Chem 140: 9–15.
  • 35
    Bussell R, Jr, Eliezer D ( 2001) Residual structure and dynamics in Parkinson's disease-associated mutants of α-synuclein. J Biol Chem 276: 45996–46003.
  • 36
    Wishart DS, Sykes BD, Richards FM ( 1992) The chemical shift index: a fast and simple method for the assignment of protein secondary structure through NMR spectroscopy. Biochemistry 31: 1647–1651.
  • 37
    Wishart DS, Sykes BD ( 1994) The 13C chemical-shift index: a simple method for the identification of protein secondary structure using 13C chemical-shift data. J Biomol NMR 4: 171–180.
  • 38
    Eliezer D ( 2007) Characterizing residual structure in disordered protein States using nuclear magnetic resonance. Methods Mol Biol 350: 49–67.
  • 39
    Uversky VN, Li J, Fink AL ( 2001) Evidence for a partially folded intermediate in α-synuclein fibril formation. J Biol Chem 276: 10737–10744.
  • 40
    Gillespie JR, Shortle D ( 1997) Characterization of long-range structure in the denatured state of staphylococcal nuclease. I. Paramagnetic relaxation enhancement by nitroxide spin labels. J Mol Biol 268: 158–169.
  • 41
    Lietzow MA, Jamin M, Dyson HJ, Wright PE ( 2002) Mapping long-range contacts in a highly unfolded protein. J Mol Biol 322: 655–662.
  • 42
    Eliezer D ( 2009) Biophysical characterization of intrinsically disordered proteins. Curr Opin Struct Biol 19: 23–30. Doi:10.1016/j.sbi.2008.12.004.
  • 43
    Sung YH, Eliezer D ( 2007) Residual structure, backbone dynamics, and interactions within the synuclein family. J Mol Biol 372: 689–707.
  • 44
    Sung YH ( 2008) Structure and interactions of the synucleins. Ph.D. thesis Cornell University Ithaca, New York, p 212.
  • 45
    Palmer AG III ( 1997) Probing molecular motion by NMR. Curr Opin Struct Biol 7: 732–737.
  • 46
    Kay LE ( 1998) Protein dynamics from NMR. Nat Struct Biol 5: 513–517.
  • 47
    Tjandra N, Bax A ( 1997) Direct measurement of distances and angles in biomolecules by NMR in a dilute liquid crystalline medium. Science 278: 1111–1114.
  • 48
    Louhivuori M, Paakkonen K, Fredriksson K, Permi P, Lounila J, Annila A ( 2003) On the origin of residual dipolar couplings from denatured proteins. J Am Chem Soc 125: 15647–15650.
  • 49
    Mohana-Borges R, Goto NK, Kroon GJ, Dyson HJ, Wright PE ( 2004) Structural characterization of unfolded states of apomyoglobin using residual dipolar couplings. J Mol Biol 340: 1131–1142.
  • 50
    Bertoncini CW, Fernandez CO, Griesinger C, Jovin TM, Zweckstetter M ( 2005) Familial mutants of α-synuclein with increased neurotoxicity have a destabilized conformation. J Biol Chem 280: 30649–30652.
  • 51
    Chiti F, Stefani M, Taddei N, Ramponi G, Dobson CM ( 2003) Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature 424: 805–808.
  • 52
    Rivers RC, Kumita JR, Tartaglia GG, Dedmon MM, Pawar A, Vendruscolo M, Dobson, CM, Christodoulou J ( 2008) Molecular determinants of the aggregation behavior of α- and β-synuclein. Protein Sci 17: 887–898.
    Direct Link:
  • 53
    Rospigliosi CC, McClendon S, Schmid AW, Ramlall TF, Barre P, Lashuel HA, Eliezer D ( 2009) The E46K Parkinson's-linked mutation enhances C-to N-terminal contacts in α-synuclein. J Mol Biol 388: 1022–1032.
  • 54
    Johnson BA, Blevins RA ( 1994) NMR View: a computer program for the visualization and analysis of NMR data. J Biomol NMR 4: 603–614.
  • 55
    Delaglio F, Grzesiek S, Vuister GW, Zhu G, Pfeifer J, Bax A ( 1995) NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J Biomol NMR 6: 277–293.
  • 56
    Wishart DS, Bigam CG, Holm A, Hodges RS, Sykes BD ( 1995) 1H, 13C and 15N random coil NMR chemical shifts of the common amino acids. I. Investigations of nearest-neighbor effects. J Biomol NMR 5: 67–81.
  • 57
    Howarth OW, Lilley DM ( 1978) Carbon-13-NMR of Peptides and Proteins. Prog NMR Spectrosc 12: 1–40.
  • 58
    Ottiger M, Delaglio F, Bax A ( 1998) Measurement of J and dipolar couplings from simplified two-dimensional NMR spectra. J Magn Reson 131: 373–378.
View Full Article (HTML) Get PDF (584K)