The aggregation of alpha-synuclein is characteristic of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. The 140-aa protein is natively unstructured; thus, ligands binding to the monomeric form are of therapeutic interest. Biogenic polyamines promote the aggregation of alpha-synuclein and may constitute endogenous agents modulating the pathogenesis of PD. We characterized the complexes of natural and synthetic polyamines with alpha-synuclein by NMR and assigned the binding site to C-terminal residues 109-140. Dissociation constants were derived from chemical shift perturbations. Greater polyamine charge (+2 --> +5) correlated with increased affinity and enhancement of fibrillation, for which we propose a simple kinetic mechanism involving a dimeric nucleation center. According to the analysis, polyamines increase the extent of nucleation by approximately 10(4) and the rate of monomer addition approximately 40-fold. Significant secondary structure is not induced in monomeric alpha-synuclein by polyamines at 15 degrees C. Instead, NMR reveals changes in a region (aa 22-93) far removed from the polyamine binding site and presumed to adopt the beta-sheet conformation characteristic of fibrillar alpha-synuclein. We conclude that the C-terminal domain acts as a regulator of alpha-synuclein aggregation.
NMR-derived models of amidopyrine and its metabolites in complexes with rabbit cytochrome P450 2B4 reveal a structural mechanism of sequential N-dealkylation.
NMR-derived models of amidopyrine and its metabolites in complexes with rabbit cytochrome P450 2B4 reveal a structural mechanism of sequential N-dealkylation.
NMR-derived models of amidopyrine and its metabolites in complexes with rabbit cytochrome P450 2B4 reveal a structural mechanism of sequential N-dealkylation.
Biochemistry. 2011 Mar 29;50(12):2123-34
Authors: Roberts AG, Sjögren SE, Fomina N, Vu KT, Almutairi A, Halpert JR
To understand the molecular basis of sequential N-dealkylation by cytochrome P450 2B enzymes, we studied the binding of...
NMR analysis of the αIIbβ3 cytoplasmic interaction suggests a mechanism for integrin regulation [Biochemistry]
NMR analysis of the αIIbβ3 cytoplasmic interaction suggests a mechanism for integrin regulation
Metcalf, D. G., Moore, D. T., Wu, Y., Kielec, J. M., Molnar, K., Valentine, K. G., Wand, A. J., Bennett, J. S., DeGrado, W. F....
Date: 2010-12-28
The integrin ?IIb?3 is a transmembrane (TM) heterodimeric adhesion receptor that exists in equilibrium between resting and active ligand binding conformations. In resting ?IIb?3, the TM and cytoplasmic domains of ?IIb and ?3 form a heterodimer that constrains ?IIb?3 in its resting conformation. To study the structure and dynamics of...
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01-03-2011 10:48 PM
NMR analysis of the {alpha}IIb{beta}3 cytoplasmic interaction suggests a mechanism for integrin regulation [Biochemistry]
NMR analysis of the {alpha}IIb{beta}3 cytoplasmic interaction suggests a mechanism for integrin regulation
Metcalf, D. G., Moore, D. T., Wu, Y., Kielec, J. M., Molnar, K., Valentine, K. G., Wand, A. J., Bennett, J. S., DeGrado, W. F....
Date: 2010-12-28
The integrin IIbβ3 is a transmembrane (TM) heterodimeric adhesion receptor that exists in equilibrium between resting and active ligand binding conformations. In resting IIbβ3, the TM and cytoplasmic domains of IIb and β3 form a heterodimer that constrains IIbβ3 in its resting conformation. To study the structure...
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12-29-2010 06:01 AM
NMR analysis of the {alpha}IIb{beta}3 cytoplasmic interaction suggests a mechanism for integrin regulation.
NMR analysis of the {alpha}IIb{beta}3 cytoplasmic interaction suggests a mechanism for integrin regulation.
NMR analysis of the {alpha}IIb{beta}3 cytoplasmic interaction suggests a mechanism for integrin regulation.
Proc Natl Acad Sci U S A. 2010 Dec 14;
Authors: Metcalf DG, Moore DT, Wu Y, Kielec JM, Molnar K, Valentine KG, Wand AJ, Bennett JS, Degrado WF
The integrin ?IIb?3 is a transmembrane (TM) heterodimeric adhesion receptor that exists in equilibrium between resting and active ligand binding conformations. In resting ?IIb?3, the TM and...
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12-16-2010 09:21 PM
[NMR paper] NMR studies on Cu(II)-peptide complexes: exchange kinetics and determination of struc
NMR studies on Cu(II)-peptide complexes: exchange kinetics and determination of structures in solution.
Related Articles NMR studies on Cu(II)-peptide complexes: exchange kinetics and determination of structures in solution.
Mol Biosyst. 2005 May;1(1):79-84
Authors: Gaggelli E, Kozlowski H, Valensin D, Valensin G
The interaction of copper(II) with histidine containing peptides has recently acquired renewed interest following the established link between abnormal protein behaviour in neurodegenerative processes and unpaired copper homeostasis....
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11-24-2010 11:14 PM
[NMR paper] Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble
Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations.
Related Articles Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations.
J Am Chem Soc. 2005 Jan 19;127(2):476-7
Authors: Dedmon MM, Lindorff-Larsen K, Christodoulou J, Vendruscolo M, Dobson CM
The intrinsically disordered protein alpha-synuclein plays a key role in the pathogenesis of Parkinson's disease (PD). We show here that the native state of alpha-synuclein...
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11-24-2010 11:14 PM
[NMR paper] 19F and 31P NMR spectroscopy of G protein alpha subunits. Mechanism of activation by
19F and 31P NMR spectroscopy of G protein alpha subunits. Mechanism of activation by Al3+ and F-.
Related Articles 19F and 31P NMR spectroscopy of G protein alpha subunits. Mechanism of activation by Al3+ and F-.
J Biol Chem. 1991 Feb 25;266(6):3396-401
Authors: Higashijima T, Graziano MP, Suga H, Kainosho M, Gilman AG
19F and 31P NMR spectroscopy was used to study the mechanism of activation of the alpha subunits of guanine nucleotide-binding regulatory proteins (G proteins) by Al3+, Mg2+, and F-. 19F NMR spectra of solutions containing Al3+,...
NMR of alpha-synuclein-polyamine complexes elucidates the mechanism and kinetics of i
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