Critical nucleus of Greek-key-like core of α-synuclein protofibril and its disruption by dopamine and norepinephrine

Zou, Yu; Qian, Zhenyu; Gong, Yehong; Tang, Yuanyan; Wei, Guanghong; Zhang, Qingwen

doi:10.1039/c9cp04610k

Cited by 25 publications

(28 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, we choose tetramer as the model of Aβ 42 protofibril in our simulation in order to save computational resources. Moreover, using the same strategy, Zou et al found that the trimer is the critical nucleus of αS 44–96 protofibril and tetramer is the smallest protofibril nucleus; hexamer is the critical nucleus and octamer is the smallest stable nucleus for the fibril of C-terminal fragment of SOD1( 147 GVIGIAQ 153 ) …”

Section: Resultsmentioning

confidence: 99%

Green Tea Extracts EGCG and EGC Display Distinct Mechanisms in Disrupting Aβ₄₂ Protofibril

Zhan

Chen

Tang

et al. 2020

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

The amyloid beta (Aβ) fibrillar aggregate is the hallmark of Alzheimer's disease (AD). Disassembling preformed fibril or inhibiting Aβ aggregation is considered as a therapeutic strategy for AD. Increasing evidence shows that green tea extracts, epigallocatechin-3-gallate (EGCG, containing an extra gallic acid ester group compared to EGC) and epigallocatechin (EGC), can disassociate Aβ fibrils and attenuate Aβ toxicity. However, the underlying molecular mechanism is poorly understood. Herein, we performed microsecond all-atom molecular dynamics (MD) simulations to investigate the influences of EGCG/EGC on the newly cryo-EM resolved LS-shaped Aβ 42 protofibrils and their detailed interactions. MD simulations demonstrate that both EGCG and EGC can disrupt Aβ 42 protofibril and EGCG displays a higher disruptive capacity than EGC. EGCG alters the L-shape of Aβ 42 protofibril by breaking the hydrogen bond between H6 and E11 through π−π interactions with residues H14/Y10 and hydrogen-bonding interactions with E11, while EGC remodels the L-shape by inserting into the hydrophobic core formed by A2, F4, L34, and V36 and via aromatics interaction with H6/Y10. EGCG disrupts the salt bridges between the K28 side chain and A42 COO − through hydrogen-bonding interaction with A42 and cation−π interaction between its gallic acid ester group and K28, while EGC damages the salt bridges through hydrophobic interactions with V39 and I41 as well as with I32, M35, and V40 located in the C-terminal hydrophobic core. This study demonstrates the pivotal role of the gallic acid ester group of EGCG in disrupting Aβ 42 protofibril and provides atomic-level insights into the distinct mechanism by which EGCG and EGC disrupt Aβ protofibril, which could be useful for designing amyloid inhibitors.

show abstract

Section: Resultsmentioning

confidence: 99%

Green Tea Extracts EGCG and EGC Display Distinct Mechanisms in Disrupting Aβ₄₂ Protofibril

Zhan

Chen

Tang

et al. 2020

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The inhibition probably activates through direct binding with the peptides and/or interfering with π–π stacking interaction between aromatic rings of amyloidogenic residues according to the observation via microscopic and quantum chemical analyses . Interestingly, some natural compounds such as taxanthin, − brazilin, − curcumin, − dopamine, − EGCG, ,,− resveratrol, ,− and rosmarinic acid − can simultaneously target the proteins involved in AD, PD, T2D, and ALS where all experimental and computational studies are reported in Table . Interestingly, although the inhibitory mechanisms of these ligands to the diseases are probably different, they all adopt a similar binding pose to Aβ peptides, α-synuclein, hIAPP, insulin, and SOD1 via molecular docking simulations (Figure ).…”

Section: Ad Pd and T2d Therapiesmentioning

confidence: 99%

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

et al. 2021

Self Cite

View full text Add to dashboard Cite

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D) and amyotrophic lateral sclerosis (ALS) research, respectively for over many years.While SOD1 is a globular protein with a well-defined 3D structure, the Aβ, tau and α-synuclein proteins belong to the class of intrinsically disordered proteins (IDPs). IDPs are also known to play a critical role in many cellular functions such as signal transduction, cell growth, binding with DNA and RNA, and transcription, and are implicated in the development of cardiovascular problems and cancers 29 . The IDPs involved in neurodegenerative diseases have a few aggregation-prone regions and overall all IDPs have a low mean hydrophobicity and a high mean net charge 30 .IDPs are structurally flexible and lack stable secondary structures in aqueous solution. When isolated, they behave as polymers in a good solvent and their radii of gyration are well described by the Flory scaling law. 31 The insolubility and high self-assembly propensity of IDPs implicated in degenerative diseases have prevented high-resolution structural determination by solution nuclear magnetic resolution (NMR) and X-ray diffraction experiments. Local information at all aggregation steps can be, however, obtained by chemical shifts, residual coupling constants, and J-couplings from NMR, exchange hydrogen/deuterium (H/D) NMR, Raman spectroscopy; and secondary structure from fast Fourier infrared spectroscopy (FTIR) or circular dichroism (CD). Long-range tertiary contacts can be deduced from paramagnetic relaxation enhancement (PRE) NMR spectroscopy and single molecule Förster resonance energy transfer (sm-FRET), and short-range distance contacts can be extracted by cross linked residues determined by mass spectrometry (MS). Low-resolution 3D information of monomers and oligomers can be obtained by ion-mobility mass-spectrometry data (IM/MS) providing cross-collision sections, dynamic light scattering (DLS), pulse field gradient NMR spectroscopy and fluorescence correlation spectroscopy (FCS) providing hydrodynamics radius, small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS), atomic force microscopy (AFM) and transmission electron microscopy (TEM) providing height features of the aggregates, as reported by some o...

show abstract

“…Here, x and y refer to the number of H-bonds and radius of gyration (Rg) of PHF6* oligomers, respectively. A contact is defined when two carbon atoms or a carbon atom and another heavy atom of two non-sequential residues lie within 0.54 nm, or any other two heavy atoms of two non-sequential residues come within 0.46 nm ( Zou et al, 2019 ; Li et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Unraveling the Influence of K280 Acetylation on the Conformational Features of Tau Core Fragment: A Molecular Dynamics Simulation Study

Zou

Guan

2021

Front. Mol. Biosci.

Self Cite

View full text Add to dashboard Cite

Abnormal aggregation of the microtubule-associated protein Tau is closely associated with tauopathies, including Alzheimer’s disease and chronic traumatic encephalopathy. The hexapeptide 275VQIINK280 (PHF6*), a fibril-nucleating core motif of Tau, has been shown to play a vital role in the aggregation of Tau. Mounting experiment evidence demonstrated the acetylation of a single-lysine residue K280 in the PHF6* was a critical event for the formation of pathological Tau amyloid deposits. However, the underlying mechanisms by which K280 acetylation affects Tau aggregation at the atomic level remain elusive. In this work, we performed replica exchange molecular dynamics simulations to investigate the influence of acetylation of K280 on the aggregation of PHF6*. Our simulations show that acetylation of K280 not only enhances the self-assembly capability of PHF6* peptides but also increases the β-sheet structure propensity of the PHF6*. The inter-molecular interactions among PHF6* peptides are strengthened by the acetylation of K280, resulting in an increased ordered β-sheet-rich conformations of the PHF6* assemblies along with a decrease of the structural diversity. The residue-pairwise contact frequency analysis shows that K280 acetylation increases the interactions among the hydrophobic chemical groups from PHF6* peptides, which promotes the aggregation of PHF6*. This study offers mechanistic insights into the effects of acetylation on the aggregation of PHF6*, which will be helpful for an in-depth understanding of the relationship between acetylation and Tau aggregation at the molecular level.

show abstract

Critical nucleus of Greek-key-like core of α-synuclein protofibril and its disruption by dopamine and norepinephrine

Abstract: Protofibrillar trimer is the critical nucleus for the αS fibril formation, and the tetramer is the minimal stable nucleus. The interactions of DA/NE with αS trimer/tetramer disrupt the backbone H-bonds and destabilize the αS protofibrils.

Cited by 25 publications

References 63 publications

Green Tea Extracts EGCG and EGC Display Distinct Mechanisms in Disrupting Aβ₄₂ Protofibril

Green Tea Extracts EGCG and EGC Display Distinct Mechanisms in Disrupting Aβ₄₂ Protofibril

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Unraveling the Influence of K280 Acetylation on the Conformational Features of Tau Core Fragment: A Molecular Dynamics Simulation Study

Contact Info

Product

Resources

About

Critical nucleus of Greek-key-like core of α-synuclein protofibril and its disruption by dopamine and norepinephrine

Abstract: Protofibrillar trimer is the critical nucleus for the αS fibril formation, and the tetramer is the minimal stable nucleus. The interactions of DA/NE with αS trimer/tetramer disrupt the backbone H-bonds and destabilize the αS protofibrils.

Cited by 25 publications

References 63 publications

Green Tea Extracts EGCG and EGC Display Distinct Mechanisms in Disrupting Aβ42 Protofibril

Green Tea Extracts EGCG and EGC Display Distinct Mechanisms in Disrupting Aβ42 Protofibril

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Unraveling the Influence of K280 Acetylation on the Conformational Features of Tau Core Fragment: A Molecular Dynamics Simulation Study

Contact Info

Product

Resources

About

Green Tea Extracts EGCG and EGC Display Distinct Mechanisms in Disrupting Aβ₄₂ Protofibril

Green Tea Extracts EGCG and EGC Display Distinct Mechanisms in Disrupting Aβ₄₂ Protofibril