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Lipid binding protein
PDB-id
1xq8
PDB id:
1xq8
Lipid binding protein
Human micelle-bound alpha-synuclein
Alpha-synuclein. Chain: a. Synonym: non-a beta component of ad amyloid, non-a4 component of amyloid, nacp. Engineered: yes
Homo sapiens. Human. Organism_taxid: 9606. Gene: snca, nacp. Expressed in: escherichia coli. Expression_system_taxid: 562.
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CATH domain
Resolution:
not givenÅ
1 models
T.S.Ulmer,A.Bax,N.B.Cole,R.L.Nussbaum
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]
Contents
NMR structure:
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Authors:
Description
Key ref:
Date:
11-Oct-04
11-Jan-05
Protein chain
Release date:
Clefts
* Residue conservation analysis
Tools
Clefts Calculation
Surface
Key reference
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.
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).
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.
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
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.
G.Veldhuis, I.Segers-Nolten, E.Ferlemann, and V.Subramaniam (2009).
Single-molecule FRET reveals structural heterogeneity of SDS-bound alpha-synuclein.
J.Yu, and Y.L.Lyubchenko (2009).
Early stages for Parkinson's development: alpha-synuclein misfolding and aggregation.
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.
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.
N.E.Robinson, M.L.Robinson, S.E.Schulze, B.T.Lai, and H.B.Gray (2009).
Deamidation of alpha-synuclein.
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.
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.
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.
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.
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.
E.Palecek, V.Ostatná, M.Masarík, C.W.Bertoncini, and T.M.Jovin (2008).
Changes in interfacial properties of alpha-synuclein preceding its aggregation.
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.
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.
M.Mihajlovic, and T.Lazaridis (2008).
Membrane-bound structure and energetics of alpha-synuclein.
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.
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.
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.
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.
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.
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.
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.
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.
K.Abe, N.Kobayashi, K.Sode, and K.Ikebukuro (2007).
Peptide ligand screening of alpha-synuclein aggregation modulators by in silico panning.
K.Beyer (2007).
Mechanistic aspects of Parkinson's disease: alpha-synuclein and the biomembrane.
K.Sode, S.Ochiai, N.Kobayashi, and E.Usuzaka (2007).
Effect of reparation of repeat sequences in the human alpha-synuclein on fibrillation ability.
O.Tcherkasskaya (2007).
Photo-activity induced by amyloidogenesis.
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.
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.
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.
J.Hardy, H.Cai, M.R.Cookson, K.Gwinn-Hardy, and A.Singleton (2006).
Genetics of Parkinson's disease and parkinsonism.
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.
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.
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.
P.Schanda, V.Forge, and B.Brutscher (2006).
HET-SOFAST NMR for fast detection of structural compactness and heterogeneity along polypeptide chains.
Y.H.Sung, and D.Eliezer (2006).
Secondary structure and dynamics of micelle bound beta- and gamma-synuclein.
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.