Small molecule induced toxic human-IAPP species characterized by NMR

Cox, S. F. J.; Camargo, Diana C. Rodriguez; Lee, Young-Ho; Dubini, Romeo C. A.; Rovó, Petra; Ivanova, Magdalena I.; Padmini, Vediappen; Reif, Bernd; Ramamoorthy, Ayyalusamy

doi:10.1039/d0cc04803h

Cited by 24 publications

(21 citation statements)

References 18 publications

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“…Understanding the mechanistic determinants of amyloid-inhibitor interaction is a prerequisite for developing new drugs, as discussed in recent reviews, 193,831 and designing new strategies to reduce the toxicities by targeting Aβ, tau, αS and IAPP. 302,[832][833][834][835][836][837][838][839][840][841][842][843][844][845][846]…”

Section: Small Molecules Polymer-based Molecules and Carbon Nanoparticlesmentioning

confidence: 99%

“…This study reported the ability of CurDac to disaggregate amyloid fibers as tested on three different amyloidogenic peptides (Aβ, IAPP and human calcitonin). 846 Toxicity measurement of the disintegrated peptide species from aged fibers, or monomers, incubated with CurDac were found to enhance the cytotoxicity of IAPP. 846 Together, these studies direct small-molecule intervention of IAPP aggregation could be lethal and need further attention and chemical optimization.…”

Section: Small Moleculesmentioning

confidence: 99%

“…846 Toxicity measurement of the disintegrated peptide species from aged fibers, or monomers, incubated with CurDac were found to enhance the cytotoxicity of IAPP. 846 Together, these studies direct small-molecule intervention of IAPP aggregation could be lethal and need further attention and chemical optimization. Like CurDac, EGCG and its stereoisomer (GCG) have been shown to be an effective inhibitor of monomeric Aβ and IAPP aggregation, remodeling toxicity of oligomers and disaggregates aged fibers in solution (Figure 30).…”

Section: Small Moleculesmentioning

confidence: 99%

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

et al. 2021

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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...

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Section: Small Molecules Polymer-based Molecules and Carbon Nanoparticlesmentioning

confidence: 99%

Section: Small Moleculesmentioning

confidence: 99%

Section: Small Moleculesmentioning

confidence: 99%

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

et al. 2021

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“…Thus, it is critical to identify compounds that modulate the deleterious interactions of IDP oligomers with membranes. In this regard, several classes of compounds have been identified to date, including small molecules ( 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ), peptides/peptidomimetics ( 18 , 19 ), molecular chaperones ( 20 , 21 , 22 , 23 , 24 , 25 ), and antibodies ( 22 , 26 ). One notable ligand that has garnered significant attention in recent years is (-)-epigallocatechin-3-gallate (EGCG).…”

mentioning

confidence: 99%

Structural determinants of the interactions of catechins with Aβ oligomers and lipid membranes

Ahmed

Huang

Lifshitz

et al. 2022

Journal of Biological Chemistry

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The aberrant self-assembly of intrinsically disordered proteins (IDPs) into soluble oligomers and their interactions with biological membranes underlie the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease. Catechins have emerged as useful tools to reduce the toxicity of IDP oligomers by modulating their interactions with membranes. However, the structural determinants of catechin binding to IDP oligomers and membranes remain largely elusive. Here, we assemble a catechin library by combining several naturally occurring chemical modifications and, using a coupled NMR-statistical approach, we map at atomic resolution the interactions of such library with the Alzheimer’s-associated amyloid-beta (Aβ) oligomers and model membranes. Our results reveal multiple catechin affinity drivers and show that the combination of affinity-reducing covalent changes may lead to unexpected net gains in affinity. Interestingly, we find that the positive cooperativity is more prevalent for Aβ oligomers than membrane binding, and that the determinants underlying catechin recognition by membranes are markedly different from those dissected for Aβ oligomers. Notably, we find that the unanticipated positive cooperativity arises from the critical regulatory role of the gallate catechin moiety, which recruits previously disengaged substituents into the binding interface and leads to an overall greater compaction of the receptor-bound conformation. Overall, the previously elusive structural attributes mapped here provide an unprecedented foundation to establish structure-activity relationships of catechins.

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“…Meanwhile, the matured fibrils may not be the major toxic species. Breaking or disassembly of preformed fibrils can induce toxicity, and CurDAc, a water-soluble curcumin derivative, induced disassembly fibrils and cell toxicity ( 39 ). However, the dialysis-related amyloidosis is known to be caused by deposition of amyloid fibrils in joint tissues ( 8 , 40 ).…”

Section: Discussionmentioning

confidence: 99%

Strong acids induce amyloid fibril formation of β2-microglobulin via an anion-binding mechanism

Yamaguchi¹,

Hasuo²,

So³

et al. 2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Small molecule induced toxic human-IAPP species characterized by NMR

Abstract: In this study, the effect of CurDAc, a water-soluble curcumin derivative, on the formation and stability of amyloid fibers is revealed. CurDAc interaction with amyloid is structurally selective, which is...

Cited by 24 publications

References 18 publications

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

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

Structural determinants of the interactions of catechins with Aβ oligomers and lipid membranes

Strong acids induce amyloid fibril formation of β2-microglobulin via an anion-binding mechanism

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