Dynamic Properties of Human α-Synuclein Related to Propensity to Amyloid Fibril Formation

Fujiwara, Satoru; Kono, Fumiaki; Matsuo, Tatsuhiro; Sugimoto, Yoshiaki; Matsumoto, Tomoharu; Narita, Akihiro; Shibata, Kaoru

doi:10.1016/j.jmb.2019.05.047

Cited by 18 publications

(28 citation statements)

References 67 publications

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“…While lipid dynamics in membranes is fairly well-understood, the short-time motions of proteins and peptides, respectively, also their influence on lipid dynamics are still unclear despite their relevance for initiating cellular processes. On one hand, various neutron scattering studies are published about antimicrobial peptides as e.g., the bee venom melittin (Sharma et al, 2015(Sharma et al, , 2016aBuck et al, 2018) or the so-called Alzheimer peptide amyloid-β (Buchsteiner et al, 2010(Buchsteiner et al, , 2012Barrett et al, 2016;Rai et al, 2016) as well as about amyloid fibrils of α-Synuclein (Fujiwara et al, 2019) (Parkinson's disease), which all three tend to damage cell membranes. On the other hand very little is known about the short-time transmembrane dynamics of proteins and peptides in membranes.…”

Section: Introductionmentioning

confidence: 99%

Lipid Dynamics in Membranes Slowed Down by Transmembrane Proteins

Ebersberger

Schindler

Kirsch

et al. 2020

Front. Cell Dev. Biol.

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Section: Introductionmentioning

confidence: 99%

Lipid Dynamics in Membranes Slowed Down by Transmembrane Proteins

Ebersberger

Schindler

Kirsch

et al. 2020

Front. Cell Dev. Biol.

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“…The QENS spectra of such samples are often analyzed using a phenomenological equation containing two Lorentzian functions so that the contributions from the local motions and those from the larger scale motions are distinguished (see below). We carried out the QENS measurements on the solution samples of hemoglobin [12], consisting of four subunits, the troponin core domain (Tn-CD) [13], containing IDRs, and α-synuclein (αSyn) [14], which is an IDP, and found that the contributions from the domain (subunit) motions as well as the segmental motions of the IDRs and the IDP could be significant. Thus, if the contributions of the diffusive motions of the entire molecules could be estimated, the contributions of the domain/segmental motions should be extracted.…”

Section: Introductionmentioning

confidence: 99%

“…The extraction of the segmental motions is critical for the characterization of the IDPs/IDRs. Previous studies on the Tn-CD [13] and αSyn [14] did not use this method, and thus the analysis of the segmental motions was qualitative. Here, we re-analyze the QENS spectra of these proteins by this method and characterize the behavior of the disordered regions in these proteins quantitatively.…”

Section: Introductionmentioning

confidence: 99%

Dynamical Behavior of Disordered Regions in Disease-Related Proteins Revealed by Quasielastic Neutron Scattering

Fujiwara

2022

Medicina

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Background and Objectives: Intrinsically disordered proteins (IDPs) and proteins containing intrinsically disordered regions (IDRs) are known to be involved in various human diseases. Since the IDPs/IDRs are fluctuating between many structural substrates, the dynamical behavior of the disease-related IDPs/IDRs needs to be characterized to elucidate the mechanisms of the pathogenesis of the diseases. As protein motions have a hierarchy ranging from local side-chain motions, through segmental motions of loops or disordered regions, to diffusive motions of entire molecules, segmental motions, as well as local motions, need to be characterized. Materials and Methods: Combined analysis of quasielastic neutron scattering (QENS) spectra with the structural data provides information on both the segmental motions and the local motions of the IDPs/IDRs. Here, this method is applied to re-analyze the QENS spectra of the troponin core domain (Tn-CD), various mutants of which cause the pathogenesis of familial cardiomyopathy (FCM), and α-synuclein (αSyn), amyloid fibril formation of which is closely related to the pathogenesis of Parkinson’s disease, collected in the previous studies. The dynamical behavior of wild-type Tn-CD, FCM-related mutant Tn-CD, and αSyn in the different propensity states for fibril formation is characterized. Results: In the Tn-CD, the behavior of the segmental motions is shown to be different between the wild type and the mutant. This difference is likely to arise from changes in the intramolecular interactions, which are suggested to be related to the functional aberration of the mutant Tn-CD. In αSyn, concerted enhancement of the segmental motions and the local motions is observed with an increased propensity for fibril formation, suggesting the importance of these motions in fibril formation. Conclusions: Characterization of the segmental motions as well as the local motions is thus useful for discussing how the changes in dynamical behavior caused by the disease-related mutations and/or environmental changes could be related to the functional and/or behavioral aberrations of these proteins.

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“…Owing to its energy range, high resolution, high intensity, and high S/N, the state-of-the-art NBS instrument is suitable for studying the dynamics of proteins. Using a time-of-flight, near-backscattering spectrometer (BL02), at the Materials and Life Science Experimental Facility at J-PARC, Japan [ 18 ], Fujiwara and Matsuo et al have published studies [ 19 , 20 , 21 , 22 , 23 , 24 ] on protein solutions, including an experiment with the world’s lowest concentration of α-Synuclein at that time (9.5 mg/mL (~0.95 wt.%)) [ 20 ]. In recent years, Inoue et al [ 25 ] and Nakagawa et al [ 26 ] reported studies on protein dynamics within protein solutions.…”

Section: Introductionmentioning

confidence: 99%

Data Collection for Dilute Protein Solutions via a Neutron Backscattering Spectrometer

Tominaga

Sahara

Oda

et al. 2022

Life

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Understanding protein functions requires not only static but also dynamic structural information. Incoherent quasi-elastic neutron scattering (QENS), which utilizes the highly incoherent scattering ability of hydrogen, is a powerful technique for revealing the dynamics of proteins in deuterium oxide (D2O) buffer solutions. The background scattering of sample cells suitable for aqueous protein solution samples, conducted with a neutron backscattering spectrometer, was evaluated. It was found that the scattering intensity of an aluminum sample cell coated with boehmite using D2O was lower than that of a sample cell coated with regular water (H2O). The D2O-Boehmite coated cell was used for the QENS measurement of a 0.8 wt.% aqueous solution of an intrinsically disordered protein in an intrinsically disordered region of a helicase-associated endonuclease for a fork-structured type of DNA. The cell was inert against aqueous samples at 283–363 K. In addition, meticulous attention to cells with small individual weight differences and the positional reproducibility of the sample cell relative to the spectrometer neutron beam position enabled the accurate subtraction of the scattering profiles of the D2O buffer and the sample container. Consequently, high-quality information on protein dynamics could be extracted from dilute protein solutions.

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Dynamic Properties of Human α-Synuclein Related to Propensity to Amyloid Fibril Formation

Cited by 18 publications

References 67 publications

Lipid Dynamics in Membranes Slowed Down by Transmembrane Proteins

Lipid Dynamics in Membranes Slowed Down by Transmembrane Proteins

Dynamical Behavior of Disordered Regions in Disease-Related Proteins Revealed by Quasielastic Neutron Scattering

Data Collection for Dilute Protein Solutions via a Neutron Backscattering Spectrometer

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