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PDBsum entry 1xq8

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protein links
Lipid binding protein PDB id
1xq8
Jmol
Contents
Protein chain
140 a.a. *
* Residue conservation analysis
PDB id:
1xq8
Name: Lipid binding protein
Title: Human micelle-bound alpha-synuclein
Structure: Alpha-synuclein. Chain: a. Synonym: non-a beta component of ad amyloid, non-a4 component of amyloid, nacp. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: snca, nacp. Expressed in: escherichia coli. Expression_system_taxid: 562.
NMR struc: 1 models
Authors: T.S.Ulmer,A.Bax,N.B.Cole,R.L.Nussbaum
Key ref:
T.S.Ulmer et al. (2005). Structure and dynamics of micelle-bound human alpha-synuclein. J Biol Chem, 280, 9595-9603. PubMed id: 15615727 DOI: 10.1074/jbc.M411805200
Date:
11-Oct-04     Release date:   11-Jan-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P37840  (SYUA_HUMAN) -  Alpha-synuclein
Seq:
Struc:
140 a.a.
140 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   28 terms 
  Biological process     cellular response to fibroblast growth factor stimulus   73 terms 
  Biochemical function     protein binding     26 terms  

 

 
DOI no: 10.1074/jbc.M411805200 J Biol Chem 280:9595-9603 (2005)
PubMed id: 15615727  
 
 
Structure and dynamics of micelle-bound human alpha-synuclein.
T.S.Ulmer, A.Bax, N.B.Cole, R.L.Nussbaum.
 
  ABSTRACT  
 
Misfolding of the protein alpha-synuclein (aS), which associates with presynaptic vesicles, has been implicated in the molecular chain of events leading to Parkinson's disease. Here, the structure and dynamics of micelle-bound aS are reported. Val3-Val37 and Lys45-Thr92 form curved alpha-helices, connected by a well ordered, extended linker in an unexpected anti-parallel arrangement, followed by another short extended region (Gly93-Lys97), overlapping the recently identified chaperone-mediated autophagy recognition motif and a highly mobile tail (Asp98-Ala140). Helix curvature is significantly less than predicted based on the native micelle shape, indicating a deformation of the micelle by aS. Structural and dynamic parameters show a reduced helical content for Ala30-Val37. A dynamic variation in interhelical distance on the microsecond timescale is complemented by enhanced sub-nanosecond timescale dynamics, particularly in the remarkably glycine-rich segments of the helices. These unusually rich dynamics may serve to mitigate the effect of aS binding on membrane fluidity. The well ordered conformation of the helix-helix connector indicates a defined interaction with lipidic surfaces, suggesting that, when bound to larger diameter synaptic vesicles, it can act as a switch between this structure and a previously proposed uninterrupted helix.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Amino acid sequence of human -synuclein (aS). The seven imperfect 11-residue repeats are labeled in Roman numerals with their second to sixth residues (predominantly KTKEGV) highlighted in red. Ser9-Ala^89 are referred to as the "repeat region" and Asp98-Ala^140 as the "tail region" of aS. Residues found to be in helical conformation in micelle-bound aS are underlined.
Figure 7.
FIG. 7. Charge distribution of micelle-bound aS. A and B, top and bottom view of the molecular surface of micelle-bound aS (average structure; Fig. 4, C-E) color-coded by electrostatic potential as depicted. The predominantly unstructured tail of aS is shown to contrast its highly acidic nature with the repeat region of aS. Electrostatic potential was calculated with APBS (70).
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 9595-9603) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21120859 A.Natalello, F.Benetti, S.M.Doglia, G.Legname, and R.Grandori (2011).
Compact conformations of α-synuclein induced by alcohols and copper.
  Proteins, 79, 611-621.  
  21290070 H.R.Lucas, and J.C.Lee (2011).
Copper(ii) enhances membrane-bound α-synuclein helix formation.
  Metallomics, 3, 280-283.  
21396938 J.Fantini, and N.Yahi (2011).
Molecular Basis for the Glycosphingolipid-Binding Specificity of α-Synuclein: Key Role of Tyrosine 39 in Membrane Insertion.
  J Mol Biol, 408, 654-669.  
21275016 M.Robotta, P.Braun, B.van Rooijen, V.Subramaniam, M.Huber, and M.Drescher (2011).
Direct evidence of coexisting horseshoe and extended helix conformations of membrane-bound alpha-synuclein.
  Chemphyschem, 12, 267-269.  
20437261 P.Manivel, J.Muthukumaran, M.Kannan, and R.Krishna (2011).
Insight into residues involved in the structure and function of the breast cancer associated protein human gamma synuclein.
  J Mol Model, 17, 251-263.  
21280118 R.L.Croke, S.M.Patil, J.Quevreaux, D.A.Kendall, and A.T.Alexandrescu (2011).
NMR determination of pK(a) values in α-synuclein.
  Protein Sci, 20, 256-269.  
21289072 Z.Cao, L.Liu, P.Wu, and J.Wang (2011).
Structural and thermodynamics characters of isolated α-syn12 peptide: long-time temperature replica-exchange molecular dynamics in aqueous solution.
  Acta Biochim Biophys Sin (Shanghai), 43, 172-180.  
  20544898 A.C.Ferreon, C.R.Moran, J.C.Ferreon, and A.A.Deniz (2010).
Alteration of the alpha-synuclein folding landscape by a mutation related to Parkinson's disease.
  Angew Chem Int Ed Engl, 49, 3469-3472.  
19802818 A.K.Bhuyan (2010).
On the mechanism of SDS-induced protein denaturation.
  Biopolymers, 93, 186-199.  
20974939 B.Greten-Harrison, M.Polydoro, M.Morimoto-Tomita, L.Diao, A.M.Williams, E.H.Nie, S.Makani, N.Tian, P.E.Castillo, V.L.Buchman, and S.S.Chandra (2010).
αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction.
  Proc Natl Acad Sci U S A, 107, 19573-19578.  
20229987 C.M.Pfefferkorn, and J.C.Lee (2010).
Tryptophan probes at the alpha-synuclein and membrane interface.
  J Phys Chem B, 114, 4615-4622.  
20203200 E.Tsika, M.Moysidou, J.Guo, M.Cushman, P.Gannon, R.Sandaltzopoulos, B.I.Giasson, D.Krainc, H.Ischiropoulos, and J.R.Mazzulli (2010).
Distinct region-specific alpha-synuclein oligomers in A53T transgenic mice: implications for neurodegeneration.
  J Neurosci, 30, 3409-3418.  
20842103 F.Kamp, N.Exner, A.K.Lutz, N.Wender, J.Hegermann, B.Brunner, B.Nuscher, T.Bartels, A.Giese, K.Beyer, S.Eimer, K.F.Winklhofer, and C.Haass (2010).
Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1.
  EMBO J, 29, 3571-3589.  
20629174 G.F.Wang, C.Li, and G.J.Pielak (2010).
19F NMR studies of α-synuclein-membrane interactions.
  Protein Sci, 19, 1686-1691.  
20730847 G.F.Wang, C.Li, and G.J.Pielak (2010).
Probing the micelle-bound aggregation-prone state of α-synuclein with (19)F NMR spectroscopy.
  Chembiochem, 11, 1993-1996.  
  20807455 J.Fantini, and N.Yahi (2010).
Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases.
  Expert Rev Mol Med, 12, e27.  
20148295 K.A.Lewis, A.Yaeger, G.N.DeMartino, and P.J.Thomas (2010).
Accelerated formation of alpha-synuclein oligomers by concerted action of the 20S proteasome and familial Parkinson mutations.
  J Bioenerg Biomembr, 42, 85-95.  
20181133 M.L.Yang, L.Hasadsri, W.S.Woods, and J.M.George (2010).
Dynamic transport and localization of alpha-synuclein in primary hippocampal neurons.
  Mol Neurodegener, 5, 9.  
20797624 S.Welker, B.Rudolph, E.Frenzel, F.Hagn, G.Liebisch, G.Schmitz, J.Scheuring, A.Kerth, A.Blume, S.Weinkauf, M.Haslbeck, H.Kessler, and J.Buchner (2010).
Hsp12 is an intrinsically unstructured stress protein that folds upon membrane association and modulates membrane function.
  Mol Cell, 39, 507-520.  
20947801 V.L.Anderson, T.F.Ramlall, C.C.Rospigliosi, W.W.Webb, and D.Eliezer (2010).
Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation.
  Proc Natl Acad Sci U S A, 107, 18850-18855.  
19293380 A.C.Ferreon, Y.Gambin, E.A.Lemke, and A.A.Deniz (2009).
Interplay of alpha-synuclein binding and conformational switching probed by single-molecule fluorescence.
  Proc Natl Acad Sci U S A, 106, 5645-5650.  
19220042 A.J.Trexler, and E.Rhoades (2009).
Alpha-synuclein binds large unilamellar vesicles as an extended helix.
  Biochemistry, 48, 2304-2306.  
  20160958 C.Chanthamontri, J.Liu, and S.A.McLuckey (2009).
Charge State Dependent Fragmentation of Gaseous alpha-Synuclein Cations via Ion Trap and Beam-Type Collisional Activation.
  Int J Mass Spectrom, 283, 9.  
19655784 C.Li, E.A.Lutz, K.M.Slade, R.A.Ruf, G.F.Wang, and G.J.Pielak (2009).
19F NMR studies of alpha-synuclein conformation and fibrillation.
  Biochemistry, 48, 8578-8584.  
19481095 C.R.Bodner, C.M.Dobson, and A.Bax (2009).
Multiple tight phospholipid-binding modes of alpha-synuclein revealed by solution NMR spectroscopy.
  J Mol Biol, 390, 775-790.  
19162471 D.Eliezer (2009).
Biophysical characterization of intrinsically disordered proteins.
  Curr Opin Struct Biol, 19, 23-30.  
19107759 G.Veldhuis, I.Segers-Nolten, E.Ferlemann, and V.Subramaniam (2009).
Single-molecule FRET reveals structural heterogeneity of SDS-bound alpha-synuclein.
  Chembiochem, 10, 436-439.  
19126542 J.D.Perlmutter, A.R.Braun, and J.N.Sachs (2009).
Curvature dynamics of alpha-synuclein familial Parkinson disease mutants: molecular simulations of the micelle- and bilayer-bound forms.
  J Biol Chem, 284, 7177-7189.  
19481090 J.N.Rao, Y.E.Kim, L.S.Park, and T.S.Ulmer (2009).
Effect of pseudorepeat rearrangement on alpha-synuclein misfolding, vesicle binding, and micelle binding.
  J Mol Biol, 390, 516-529.  
18633713 J.Yu, and Y.L.Lyubchenko (2009).
Early stages for Parkinson's development: alpha-synuclein misfolding and aggregation.
  J Neuroimmune Pharmacol, 4, 10-16.  
19099437 K.G.Urie, D.Angulo, J.C.Lee, J.J.Kozak, H.B.Gray, and J.R.Winkler (2009).
Synchronous vs asynchronous chain motion in alpha-synuclein contact dynamics.
  J Phys Chem B, 113, 522-530.  
19576220 K.P.Wu, D.S.Weinstock, C.Narayanan, R.M.Levy, and J.Baum (2009).
Structural reorganization of alpha-synuclein at low pH observed by NMR and REMD simulations.
  J Mol Biol, 391, 784-796.  
19285989 K.Vamvaca, M.J.Volles, and P.T.Lansbury (2009).
The first N-terminal amino acids of alpha-synuclein are essential for alpha-helical structure formation in vitro and membrane binding in yeast.
  J Mol Biol, 389, 413-424.  
19348768 L.Kjaer, L.Giehm, T.Heimburg, and D.Otzen (2009).
The influence of vesicle size and composition on alpha-synuclein structure and stability.
  Biophys J, 96, 2857-2870.  
19669606 M.Bisaglia, I.Tessari, S.Mammi, and L.Bubacco (2009).
Interaction between alpha-synuclein and metal ions, still looking for a role in the pathogenesis of Parkinson's disease.
  Neuromolecular Med, 11, 239-251.  
19116775 M.Y.Golovko, G.Barceló-Coblijn, P.I.Castagnet, S.Austin, C.K.Combs, and E.J.Murphy (2009).
The role of alpha-synuclein in brain lipid metabolism: a downstream impact on brain inflammatory response.
  Mol Cell Biochem, 326, 55-66.  
19521992 N.E.Robinson, M.L.Robinson, S.E.Schulze, B.T.Lai, and H.B.Gray (2009).
Deamidation of alpha-synuclein.
  Protein Sci, 18, 1766-1773.  
19278224 P.E.Smith, J.R.Brender, and A.Ramamoorthy (2009).
Induction of negative curvature as a mechanism of cell toxicity by amyloidogenic peptides: the case of islet amyloid polypeptide.
  J Am Chem Soc, 131, 4470-4478.  
19177358 R.C.Page, S.Lee, J.D.Moore, S.J.Opella, and T.A.Cross (2009).
Backbone structure of a small helical integral membrane protein: A unique structural characterization.
  Protein Sci, 18, 134-146.
PDB code: 2k3m
19995078 R.P.Nanga, J.R.Brender, S.Vivekanandan, N.Popovych, and A.Ramamoorthy (2009).
NMR structure in a membrane environment reveals putative amyloidogenic regions of the SEVI precursor peptide PAP(248-286).
  J Am Chem Soc, 131, 17972-17979.
PDB code: 2l3h
18980610 T.Ben Gedalya, V.Loeb, E.Israeli, Y.Altschuler, D.J.Selkoe, and R.Sharon (2009).
alpha-Synuclein and Polyunsaturated Fatty Acids Promote Clathrin-Mediated Endocytosis and Synaptic Vesicle Recycling.
  Traffic, 10, 218-234.  
19730729 T.F.Outeiro, J.Klucken, K.Bercury, J.Tetzlaff, P.Putcha, L.M.Oliveira, A.Quintas, P.J.McLean, and B.T.Hyman (2009).
Dopamine-induced conformational changes in alpha-synuclein.
  PLoS One, 4, e6906.  
19279667 T.L.Lau, C.Kim, M.H.Ginsberg, and T.S.Ulmer (2009).
The structure of the integrin alphaIIbbeta3 transmembrane complex explains integrin transmembrane signalling.
  EMBO J, 28, 1351-1361.
PDB code: 2k9j
19555081 V.Vandelinder, A.C.Ferreon, Y.Gambin, A.A.Deniz, and A.Groisman (2009).
High-resolution temperature-concentration diagram of alpha-synuclein conformation obtained from a single Förster resonance energy transfer image in a microfluidic device.
  Anal Chem, 81, 6929-6935.  
18952168 A.K.Dunker, I.Silman, V.N.Uversky, and J.L.Sussman (2008).
Function and structure of inherently disordered proteins.
  Curr Opin Struct Biol, 18, 756-764.  
19066219 C.C.Jao, B.G.Hegde, J.Chen, I.S.Haworth, and R.Langen (2008).
Structure of membrane-bound alpha-synuclein from site-directed spin labeling and computational refinement.
  Proc Natl Acad Sci U S A, 105, 19666-19671.  
18087617 E.Palecek, V.Ostatná, M.Masarík, C.W.Bertoncini, and T.M.Jovin (2008).
Changes in interfacial properties of alpha-synuclein preceding its aggregation.
  Analyst, 133, 76-84.  
18774805 E.R.Georgieva, T.F.Ramlall, P.P.Borbat, J.H.Freed, and D.Eliezer (2008).
Membrane-bound alpha-synuclein forms an extended helix: long-distance pulsed ESR measurements using vesicles, bicelles, and rodlike micelles.
  J Am Chem Soc, 130, 12856-12857.  
18769546 I.F.Tsigelny, L.Crews, P.Desplats, G.M.Shaked, Y.Sharikov, H.Mizuno, B.Spencer, E.Rockenstein, M.Trejo, O.Platoshyn, J.X.Yuan, and E.Masliah (2008).
Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases.
  PLoS ONE, 3, e3135.  
18640077 I.F.Tsigelny, Y.Sharikov, M.A.Miller, and E.Masliah (2008).
Mechanism of alpha-synuclein oligomerization and membrane interaction: theoretical approach to unstructured proteins studies.
  Nanomedicine, 4, 350-357.  
18343814 K.E.Paleologou, A.W.Schmid, C.C.Rospigliosi, H.Y.Kim, G.R.Lamberto, R.A.Fredenburg, P.T.Lansbury, C.O.Fernandez, D.Eliezer, M.Zweckstetter, and H.A.Lashuel (2008).
Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of alpha-synuclein.
  J Biol Chem, 283, 16895-16905.  
17729279 M.Mihajlovic, and T.Lazaridis (2008).
Membrane-bound structure and energetics of alpha-synuclein.
  Proteins, 70, 761-778.  
18198943 M.Sandal, F.Valle, I.Tessari, S.Mammi, E.Bergantino, F.Musiani, M.Brucale, L.Bubacco, and B.Samorì (2008).
Conformational equilibria in monomeric alpha-Synuclein at the single-molecule level.
  PLoS Biol, 6, e6.  
18550842 M.Vilar, H.T.Chou, T.Lührs, S.K.Maji, D.Riek-Loher, R.Verel, G.Manning, H.Stahlberg, and R.Riek (2008).
The fold of alpha-synuclein fibrils.
  Proc Natl Acad Sci U S A, 105, 8637-8642.  
18248604 P.Bar-On, L.Crews, A.O.Koob, H.Mizuno, A.Adame, B.Spencer, and E.Masliah (2008).
Statins reduce neuronal alpha-synuclein aggregation in in vitro models of Parkinson's disease.
  J Neurochem, 105, 1656-1667.  
18436957 R.C.Rivers, J.R.Kumita, G.G.Tartaglia, M.M.Dedmon, A.Pawar, M.Vendruscolo, C.M.Dobson, and J.Christodoulou (2008).
Molecular determinants of the aggregation behavior of alpha- and beta-synuclein.
  Protein Sci, 17, 887-898.  
18493022 R.L.Croke, C.O.Sallum, E.Watson, E.D.Watt, and A.T.Alexandrescu (2008).
Hydrogen exchange of monomeric alpha-synuclein shows unfolded structure persists at physiological temperature and is independent of molecular crowding in Escherichia coli.
  Protein Sci, 17, 1434-1445.  
18808659 S.Wislet-Gendebien, N.P.Visanji, S.N.Whitehead, D.Marsilio, W.Hou, D.Figeys, P.E.Fraser, S.A.Bennett, and A.Tandon (2008).
Differential regulation of wild-type and mutant alpha-synuclein binding to synaptic membranes by cytosolic factors.
  BMC Neurosci, 9, 92.  
18537543 V.N.Uversky (2008).
Amyloidogenesis of natively unfolded proteins.
  Curr Alzheimer Res, 5, 260-287.  
17381514 I.F.Tsigelny, P.Bar-On, Y.Sharikov, L.Crews, M.Hashimoto, M.A.Miller, S.H.Keller, O.Platoshyn, J.X.Yuan, and E.Masliah (2007).
Dynamics of alpha-synuclein aggregation and inhibition of pore-like oligomer development by beta-synuclein.
  FEBS J, 274, 1862-1877.  
17279794 J.C.Lee, B.T.Lai, J.J.Kozak, H.B.Gray, and J.R.Winkler (2007).
Alpha-synuclein tertiary contact dynamics.
  J Phys Chem B, 111, 2107-2112.  
17554782 J.M.Crowet, L.Lins, I.Dupiereux, B.Elmoualija, A.Lorin, B.Charloteaux, V.Stroobant, E.Heinen, and R.Brasseur (2007).
Tilted properties of the 67-78 fragment of alpha-synuclein are responsible for membrane destabilization and neurotoxicity.
  Proteins, 68, 936-947.  
18005454 K.Abe, N.Kobayashi, K.Sode, and K.Ikebukuro (2007).
Peptide ligand screening of alpha-synuclein aggregation modulators by in silico panning.
  BMC Bioinformatics, 8, 451.  
17652776 K.Beyer (2007).
Mechanistic aspects of Parkinson's disease: alpha-synuclein and the biomembrane.
  Cell Biochem Biophys, 47, 285-299.  
  17200685 K.Sode, S.Ochiai, N.Kobayashi, and E.Usuzaka (2007).
Effect of reparation of repeat sequences in the human alpha-synuclein on fibrillation ability.
  Int J Biol Sci, 3, 1-7.  
17327395 O.Tcherkasskaya (2007).
Photo-activity induced by amyloidogenesis.
  Protein Sci, 16, 561-571.  
17456743 S.Zibaee, O.S.Makin, M.Goedert, and L.C.Serpell (2007).
A simple algorithm locates beta-strands in the amyloid fibril core of alpha-synuclein, Abeta, and tau using the amino acid sequence alone.
  Protein Sci, 16, 906-918.  
17681534 Y.H.Sung, and D.Eliezer (2007).
Residual structure, backbone dynamics, and interactions within the synuclein family.
  J Mol Biol, 372, 689-707.  
16452621 B.C.McNulty, A.Tripathy, G.B.Young, L.M.Charlton, J.Orans, and G.J.Pielak (2006).
Temperature-induced reversible conformational change in the first 100 residues of alpha-synuclein.
  Protein Sci, 15, 602-608.  
16420483 C.Farès, D.S.Libich, and G.Harauz (2006).
Solution NMR structure of an immunodominant epitope of myelin basic protein. Conformational dependence on environment of an intrinsically unstructured protein.
  FEBS J, 273, 601-614.  
17068789 J.Hardy, H.Cai, M.R.Cookson, K.Gwinn-Hardy, and A.Singleton (2006).
Genetics of Parkinson's disease and parkinsonism.
  Ann Neurol, 60, 389-398.  
16731975 M.Bisaglia, A.Trolio, M.Bellanda, E.Bergantino, L.Bubacco, and S.Mammi (2006).
Structure and topology of the non-amyloid-beta component fragment of human alpha-synuclein bound to micelles: implications for the aggregation process.
  Protein Sci, 15, 1408-1416.  
16411187 M.Bisaglia, E.Schievano, A.Caporale, E.Peggion, and S.Mammi (2006).
The 11-mer repeats of human alpha-synuclein in vesicle interactions and lipid composition discrimination: a cooperative role.
  Biopolymers, 84, 310-316.  
16895578 P.Bar-On, E.Rockenstein, A.Adame, G.Ho, M.Hashimoto, and E.Masliah (2006).
Effects of the cholesterol-lowering compound methyl-beta-cyclodextrin in models of alpha-synucleinopathy.
  J Neurochem, 98, 1032-1045.  
16823898 P.Schanda, V.Forge, and B.Brutscher (2006).
HET-SOFAST NMR for fast detection of structural compactness and heterogeneity along polypeptide chains.
  Magn Reson Chem, 44, S177-S184.  
16597821 Y.H.Sung, and D.Eliezer (2006).
Secondary structure and dynamics of micelle bound beta- and gamma-synuclein.
  Protein Sci, 15, 1162-1174.  
15944734 J.Bigay, J.F.Casella, G.Drin, B.Mesmin, and B.Antonny (2005).
ArfGAP1 responds to membrane curvature through the folding of a lipid packing sensor motif.
  EMBO J, 24, 2244-2253.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.