Structure and Dynamics of Micelle-bound Human α-Synuclein

Ulmer, Tobias S.; Bax, Ad; Cole, Nelson B.; Nussbaum, Robert L.

doi:10.1074/jbc.m411805200

Cited by 861 publications

(1,289 citation statements)

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“…2(B)] are consistent both with this conclusion and with conclusions based on 15 N NMR data, which show that the N-terminal region of the protein binds SDS while the C-terminal region remains disordered. 13,20,24,28,31,32 Solution NMR is a powerful tool for accessing processes that occur over a range of timescales. 26 In 250 mM NaCl, SDS forms larger rod-like micelles, decreasing the tumbling rate of the a-synuclein-micelle complex.…”

Section: Resultsmentioning

confidence: 99%

“…[8][9][10][11][12] The protein binds lipids and anionic detergents through the seven imperfect, cationic, 11-amino acid repeats located in its N-terminal and hydrophobic regions. [6][7][8][13][14][15][16][17][18][19][20] Electron paramagnetic resonance (EPR) data on its complex with small unilamellar vesicles (SUVs) suggest that the first $100 residues of the monomeric protein adopt an a-helical conformation that lies on the membrane surface. [21][22][23][24][25] The last $40 residues lack defined structure and do not appear to be involved in membrane interactions.…”

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confidence: 99%

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¹⁹F NMR studies of α‐synuclein‐membrane interactions

Wang

Pielak

2010

Protein Science

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a-Synuclein function is thought to be related to its membrane binding ability. Solution NMR studies have identified several a-synuclein-membrane interaction modes in small unilamellar vesicles (SUVs), but how membrane properties affect binding remains unclear. Here, we use 19 F NMR to study a-synuclein-membrane interactions by using 3-fluoro-L-tyrosine (3FY) and trifluoromethyl-Lphenylalanine (tfmF) labeled proteins. Our results indicate that the affinity is affected by both the head group and the acyl chain of the SUV. Negatively charged head groups have higher affinity, but different head groups with the same charge also affect binding. We show that the saturation of the acyl chain has a dramatic effect on the a-synuclein-membrane interactions by studying lipids with the same head group but different chains. Taken together, the data show that a-synuclein's N-terminal region is the most important determinate of SUV binding, but its C-terminal region also modulates the interactions. Our data support the existence of multiple tight phospholipid-binding modes, a result incompatible with the model that a-synuclein lies solely on the membrane surface.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

¹⁹F NMR studies of α‐synuclein‐membrane interactions

Wang

Pielak

2010

Protein Science

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“…Indeed, triplication of the αS locus was shown to cause PD and αS progressively accumulates in cytosolic vesicles and the ER during disease (Cooper et al, 2006;Colla et al, 2012). Moreover, the C-terminal tail of Rab8a is less affected by nucleotide and membrane binding and can therefore -independent of other Rab8a interactions -contribute to the interaction with the C-terminal domain of αS, which remains accessible in both the soluble and membrane-bound states and even in αS fibrils (Del Mar et al, 2005;Eliezer et al, 2001;Ulmer et al, 2005;Vilar et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Intra-and intermolecular contacts can be detected in monomeric, unfolded αS and are implicated in modulating the aggregation propensity (Bertoncini et al, 2005;Dedmon et al, 2005;Outeiro et al, 2008;Wu and Baum, 2010). The negatively charged C-terminus remains disordered in several conformational states such as monomeric, fibrillar and membrane-bound αS (Del Mar et al, 2005;Eliezer et al, 2001;Qin et al, 2007;Ulmer et al, 2005;Vilar et al, 2008). In Lewy õbodies, 90% of αS is estimated to be phosphorylated at S129 in the C-terminus (Fujiwara et al, 2002).…”

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confidence: 99%

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Yin¹,

Fonseca²,

Eisbach³

et al. 2014

Neurobiology of Disease

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Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 -the Drosophila ortholog of Rab8a -ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS-Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.

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“…RDCs have provided particularly important results in studies on IDPs. Jensen et al 2013;Ulmer et al 2005).…”

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confidence: 99%

Protein dynamics and function from solution state NMR spectroscopy

Kovermann

Rogne

Wolf‐Watz

2016

Quart. Rev. Biophys.

143

122

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Abstract. It is well-established that dynamics are central to protein function; their importance is implicitly acknowledged in the principles of the Monod, Wyman and Changeux model of binding cooperativity, which was originally proposed in 1965. Nowadays the concept of protein dynamics is formulated in terms of the energy landscape theory, which can be used to understand protein folding and conformational changes in proteins. Because protein dynamics are so important, a key to understanding protein function at the molecular level is to design experiments that allow their quantitative analysis. Nuclear magnetic resonance (NMR) spectroscopy is uniquely suited for this purpose because major advances in theory, hardware, and experimental methods have made it possible to characterize protein dynamics at an unprecedented level of detail. Unique features of NMR include the ability to quantify dynamics (i) under equilibrium conditions without external perturbations, (ii) using many probes simultaneously, and (iii) over large time intervals. Here we review NMR techniques for quantifying protein dynamics on fast (ps-ns), slow (μs-ms), and very slow (s-min) time scales. These techniques are discussed with reference to some major discoveries in protein science that have been made possible by NMR spectroscopy.

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Structure and Dynamics of Micelle-bound Human α-Synuclein

Cited by 861 publications

References 70 publications

¹⁹F NMR studies of α‐synuclein‐membrane interactions

¹⁹F NMR studies of α‐synuclein‐membrane interactions

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Protein dynamics and function from solution state NMR spectroscopy

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Structure and Dynamics of Micelle-bound Human α-Synuclein

Cited by 861 publications

References 70 publications

19F NMR studies of α‐synuclein‐membrane interactions

19F NMR studies of α‐synuclein‐membrane interactions

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Protein dynamics and function from solution state NMR spectroscopy

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¹⁹F NMR studies of α‐synuclein‐membrane interactions

¹⁹F NMR studies of α‐synuclein‐membrane interactions