2,551 results match your criteria abeta fibrils


[Cell-surface Initial Aggregation Process of Amyloid-β Peptides Studied by Fluorescence Correlation Spectroscopy].

Authors:
Yoshiaki Yano

Yakugaku Zasshi 2021 ;141(6):825-829

Department of Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University.

The formation of neurotoxic aggregates by amyloid-β peptide (Aβ) is considered to be a key step in the onset of Alzheimer's disease. It is widely accepted that oligomers are more neurotoxic than amyloid fibrils in the aqueous-phase aggregation of Aβ. Membrane-mediated amyloidogenesis is also relevant to the pathology, although the relationship between the aggregate size and cytotoxicity has remained elusive. Read More

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January 2021

(-)-Oleocanthal Nutraceuticals for Alzheimer's Disease Amyloid Pathology: Novel Oral Formulations, Therapeutic, and Molecular Insights in 5xFAD Transgenic Mice Model.

Nutrients 2021 May 18;13(5). Epub 2021 May 18.

School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA.

Alzheimer's disease (AD) is a complex progressive neurodegenerative disorder affecting humans mainly through the deposition of Aβ-amyloid (Aβ) fibrils and accumulation of neurofibrillary tangles in the brain. Currently available AD treatments only exhibit symptomatic relief but do not generally intervene with the amyloid and tau pathologies. The extra-virgin olive oil (EVOO) monophenolic secoiridoid -(-)-oleocanthal (OC) showed anti-inflammatory activity through COX system inhibition with potency comparable to the standard non-steroidal anti-inflammatory drug (NSAID) like ibuprofen. Read More

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Structural Studies Providing Insights into Production and Conformational Behavior of Amyloid-β Peptide Associated with Alzheimer's Disease Development.

Molecules 2021 May 13;26(10). Epub 2021 May 13.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia.

Alzheimer's disease is the most common type of neurodegenerative disease in the world. Genetic evidence strongly suggests that aberrant generation, aggregation, and/or clearance of neurotoxic amyloid-β peptides () triggers the disease. accumulates at the points of contact of neurons in ordered cords and fibrils, forming the so-called senile plaques. Read More

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Calcium Dyshomeostasis in Alzheimer's Disease Pathogenesis.

Int J Mol Sci 2021 May 6;22(9). Epub 2021 May 6.

Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder that is characterized by amyloid β-protein deposition in senile plaques, neurofibrillary tangles consisting of abnormally phosphorylated tau protein, and neuronal loss leading to cognitive decline and dementia. Despite extensive research, the exact mechanisms underlying AD remain unknown and effective treatment is not available. Many hypotheses have been proposed to explain AD pathophysiology; however, there is general consensus that the abnormal aggregation of the amyloid β peptide (Aβ) is the initial event triggering a pathogenic cascade of degenerating events in cholinergic neurons. Read More

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PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) ameliorate learning and memory deficit in a rat model of Alzheimer's disease: Potential participation of STIMs.

Neurotoxicology 2021 Jul 29;85:145-159. Epub 2021 May 29.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 1416753955, Iran. Electronic address:

The amyloid-beta (Aβ) fibrillation process seems to execute a principal role in the neuropathology of Alzheimer's disease (AD). Accordingly, novel therapeutic plans have concentrated on the inhibition or degradation of Aβ oligomers and fibrils. Biocompatible nanoparticles (NPs), e. Read More

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Super-resolution imaging reveals α-synuclein seeded aggregation in SH-SY5Y cells.

Commun Biol 2021 05 21;4(1):613. Epub 2021 May 21.

Department of Chemistry, University of Cambridge, Cambridge, UK.

Aggregation of α-synuclein (α-syn) is closely linked to Parkinson's disease (PD) and the related synucleinopathies. Aggregates spread through the brain during the progression of PD, but the mechanism by which this occurs is still not known. One possibility is a self-propagating, templated-seeding mechanism, but this cannot be established without quantitative information about the efficiencies and rates of the key steps in the cellular process. Read More

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Inhibitory Effects of Sulfated Polysaccharides from the Sea Cucumber against Aβ40 Aggregation and Cytotoxicity.

ACS Chem Neurosci 2021 06 17;12(11):1854-1859. Epub 2021 May 17.

Institute of Oceanography, Minjiang University, Fuzhou, Fujian 350108, China.

Abnormal aggregation and deposition of Aβ is one of the causative agents for Alzheimer's disease. The development of inhibitors for Aβ aggregation has been considered a possible method to prevent and treat Alzheimer's disease. Edible sea cucumbers contain many bioactive molecules, including saponins, phospholipids, peptides, and polysaccharides. Read More

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EGFR Aggregation in the Brain.

ACS Chem Neurosci 2021 06 12;12(11):1833-1834. Epub 2021 May 12.

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Recent findings showed that preformed fibrils (PFFs) of misfolded proteins, including α-synuclein (α-syn) and amyloid-β (Aβ), activate EGFR in cell cultures and animal models of amyloid propagation. Comparing these supramolecular structures to normal EGFR ligands such as EGF and HB-EGF suggests that these PFFs might trigger the formation of high order clustering of EGFR that stimulates the aggregation of EGFR tyrosine kinase domain (EGFR-TKD) which is known to form fibrils. Subsequently, self-assembled fibril of EGFR-TKDs itself can serve as a seed to induce aggregation of monomeric forms of misfolded proteins in cytoplasm or endosomes. Read More

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Procyanidine resists the fibril formation of human islet amyloid polypeptide.

Int J Biol Macromol 2021 Jul 7;183:1067-1078. Epub 2021 May 7.

Department of Chemistry, Renmin University of China, Beijing 100872, China. Electronic address:

Human islet amyloid polypeptide (hIAPP) is widely studied due to its close correlation with the pathogenic mechanism of type II diabetes mellitus (T2DM). Bioflavonoids have been used in the neurodegeneration and diabetes studies. However, the structure-activity relationship remains unclear in many of these compounds. Read More

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Promoted Aggregation of Aβ on Lipid Bilayers in an Open Flowing System.

J Phys Chem Lett 2021 May 6;12(18):4453-4460. Epub 2021 May 6.

Faculty of Science, Yamagata University, 1-4-12 Kojirakawa, Yamagata 990-8560, Japan.

Self-assembly of amyloid-β (Aβ) peptides in nonequilibrium, flowing conditions is associated with pathogenesis of Alzheimer's disease. We examined the role of biologically relevant, nonequilibrium, flowing conditions in the desorption, diffusion, and integration of Aβ-lipid assemblies at the membrane surface using a microchannel connected with microsyringes. A 1,2-dimyristoyl--glycero-3-phosphocholine (DMPC) bilayer was formed on a glass substrate and incubated in Aβ solution under either a quiescent condition (no flow) or flowing condition for 24 h. Read More

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Spontaneous Formation of β-sheet Nano-barrels during the Early Aggregation of Alzheimer's Amyloid Beta.

Nano Today 2021 Jun 13;38. Epub 2021 Mar 13.

Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, United States.

Soluble low-molecular-weight oligomers formed during the early aggregation of amyloid peptides have been hypothesized as a major toxic species of amyloidogenesis. Herein, we performed the first synergic , and validations of the structure, dynamics and toxicity of Aβ42 oligomers. Aβ peptides readily assembled into β-rich oligomers comprised of extended β-hairpins and β-strands. Read More

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Development of molecular tools for diagnosis of Alzheimer's disease that are based on detection of amyloidogenic proteins.

Prion 2021 Dec;15(1):56-69

Laboratory of Amyloid Biology, St. Petersburg State University, St. Petersburg, Russia.

Alzheimer's disease (AD) is the most common form of dementia that usually occurs among older people. AD results from neuronal degeneration that leads to the cognitive impairment and death. AD is incurable, typically develops over the course of many years and is accompanied by a loss of functional autonomy, making a patient completely dependent on family members and/or healthcare workers. Read More

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December 2021

Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation.

Acta Biochim Pol 2021 Apr;68(2):169-179

Department of Biochemistry and Biophysics, Stockholm University, Sweden.

Alzheimer's disease (AD) is an incurable disease and the main cause of age-related dementia worldwide, despite decades of research. Treatment of AD with lithium (Li) has showed promising results, but the underlying mechanism is unclear. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils. Read More

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Conformation-specific perturbation of membrane dynamics by structurally distinct oligomers of Alzheimer's amyloid-β peptide.

Phys Chem Chem Phys 2021 Apr;23(16):9686-9694

Centre for Protein Science Design and Engineering, Indian Institute of Science Education and Research (IISER), Mohali 140306, Punjab, India.

The accumulation of toxic soluble oligomers of the amyloid-β peptide (Aβ) is a key step in the pathogenesis of Alzheimer's disease. There are mainly two conformationally distinct oligomers, namely, prefibrillar and fibrillar oligomers, that are recognized by conformation-specific antibodies, anti-amyloid oligomer antibody (A11) and anti-amyloid fibrillar antibody (OC), respectively. Previous studies have shown that the interaction of Aβ oligomers with the lipid membrane is one of the key mechanisms of toxicity produced by Aβ oligomers. Read More

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Defining the Landscape of the Pauling-Corey Rippled Sheet: An Orphaned Motif Finding New Homes.

Acc Chem Res 2021 05 26;54(10):2488-2501. Epub 2021 Apr 26.

Department of Chemistry, University of Rochester, Rochester, New York 14627-0216, United States.

When peptides are mixed with their mirror images in an equimolar ratio, two-dimensional periodic structural folds can form, in which extended peptide strands are arrayed with alternating chirality. The resultant topography class, termed the rippled β-sheet, was introduced as a theoretical concept by Pauling and Corey in 1953. Unlike other fundamental protein structural motifs identified around that time, including the α-helix and the pleated β-sheet, it took several decades before conclusive experimental data supporting the proposed rippled β-sheet motif were gained. Read More

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Identification of a nanomolar affinity α-synuclein fibril imaging probe by ultra-high throughput screening.

Chem Sci 2020 Dec 10;11(47):12746-12754. Epub 2020 Sep 10.

Department of Chemistry , University of Pennsylvania , 231 South 34th Street , Philadelphia , PA 19104 , USA . Email:

Small molecules that bind with high affinity and specificity to fibrils of the α-synuclein (αS) protein have the potential to serve as positron emission tomography (PET) imaging probes to aid in the diagnosis of Parkinson's disease and related synucleinopathies. To identify such molecules, we employed an ultra-high throughput screening strategy using idealized pseudo-ligands termed exemplars to identify compounds for experimental binding studies. For the top hit from this screen, we used photo-crosslinking to confirm its binding site and studied the structure-activity relationship of its analogs to develop multiple molecules with nanomolar affinity for αS fibrils and moderate specificity for αS over Aβ fibrils. Read More

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December 2020

C subunit of the ATP synthase is an amyloidogenic calcium dependent channel-forming peptide with possible implications in mitochondrial permeability transition.

Sci Rep 2021 Apr 22;11(1):8744. Epub 2021 Apr 22.

Department of Molecular Pathobiology, New York University College of Dentistry, 345 East 24th Street, New York, NY, 10010-4086, USA.

The c subunit is an inner mitochondrial membrane (IMM) protein encoded by three nuclear genes. Best known as an integral part of the F complex of the ATP synthase, the c subunit is also present in other cytoplasmic compartments in ceroid lipofuscinoses. Under physiological conditions, this 75 residue-long peptide folds into an α-helical hairpin and forms oligomers spanning the lipid bilayer. Read More

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Nonphosphorylated tau slows down Aβ aggregation, binds to Aβ oligomers, and reduces Aβ toxicity.

J Biol Chem 2021 Jan-Jun;296:100664. Epub 2021 Apr 16.

Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. Electronic address:

The formation of neurofibrillary tangles and amyloid plaques accompanies the progression of Alzheimer's disease. Tangles are made of fibrillar aggregates formed by the microtubule-associated protein tau, whereas plaques comprise fibrillar forms of amyloid-beta (Aβ). Both form toxic oligomers during aggregation and are thought to interact synergistically to each promote the accumulation of the other. Read More

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A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody.

Alzheimers Res Ther 2021 04 17;13(1):80. Epub 2021 Apr 17.

Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA.

Background: Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia.

Methods: BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. Read More

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Lipid membranes induce structural conversion from amyloid oligomers to fibrils.

Authors:
Lei Gu Zhefeng Guo

Biochem Biophys Res Commun 2021 06 14;557:122-126. Epub 2021 Apr 14.

Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA, 90095, USA. Electronic address:

Formation of amyloid oligomers and fibrils underlies the pathogenesis of a number of neurodegenerative diseases such as Alzheimer's. One mechanism of action by which Aβ aggregates cause neuronal toxicity is through interactions with cellular membranes. Aβ aggregates have been shown to disrupt membrane integrity via pore formation, membrane thinning, or lipid extraction. Read More

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Near-Infrared-Active Copper Molybdenum Sulfide Nanocubes for Phonon-Mediated Clearance of Alzheimer's β-Amyloid Aggregates.

ACS Appl Mater Interfaces 2021 Apr 16;13(16):18581-18593. Epub 2021 Apr 16.

Department of Materials Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), 335 Science Road, Daejeon 34141, Republic of Korea.

Ternary chalcogenide materials have attracted significant interest in recent years because of their unique physicochemical and optoelectronic properties without relying on precious metals, rare earth metals, or toxic elements. Copper molybdenum sulfide (CuMoS, CMS) nanocube is a biocompatible ternary chalcogenide nanomaterial that exhibits near-infrared (NIR) photocatalytic activity based on its low band gap and electron-phonon coupling property. Here, we study the efficacy of CMS nanocubes for dissociating neurotoxic Alzheimer's β-amyloid (Aβ) aggregates under NIR light. Read More

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Unexpected Function of a Heptapeptide-Conjugated Zwitterionic Polymer that Coassembles into β-Amyloid Fibrils and Eliminates the Amyloid Cytotoxicity.

ACS Appl Mater Interfaces 2021 Apr 8;13(15):18089-18099. Epub 2021 Apr 8.

Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China.

Fibrillogenesis of amyloid β-protein (Aβ) is pathologically associated with Alzheimer's disease (AD), so modulating Aβ aggregation is crucial for AD prevention and treatment. Herein, a zwitterionic polymer with short dimethyl side chains (pID) is synthesized and conjugated with a heptapeptide inhibitor (Ac-LVFFARK-NH, LK7) to construct zwitterionic polymer-inhibitor conjugates for enhanced inhibition of Aβ aggregation. However, it is unexpectedly found that the [email protected] conjugates remarkably promote Aβ fibrillization to form more fibrils than the free Aβ system but effectively eliminate Aβ-induced cytotoxicity. Read More

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Biflavonoid-Induced Disruption of Hydrogen Bonds Leads to Amyloid-β Disaggregation.

Int J Mol Sci 2021 Mar 12;22(6). Epub 2021 Mar 12.

Department of Pharmacology, A.T. Still University, Kirksville, MO 63501, USA.

Deposition of amyloid β (Aβ) fibrils in the brain is a key pathologic hallmark of Alzheimer's disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aβ and promoting disaggregation of Aβ fibrils. In the present study, we further sought to investigate the structural basis of the Aβ disaggregating activity of biflavonoids and their interactions at the atomic level. Read More

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Extract from the Marine Seaweed Protects Mitochondrial Biomembranes from Damage by Amyloidogenic Peptides.

Molecules 2021 Mar 7;26(5). Epub 2021 Mar 7.

Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, 2023 Msida, Malta.

The identification of compounds which protect the double-membrane of mitochondrial organelles from disruption by toxic confomers of amyloid proteins may offer a therapeutic strategy to combat human neurodegenerative diseases. Here, we exploited an extract from the marine brown seaweed (PPE) as a vital source of natural bioactive compounds to protect mitochondrial membranes against insult by oligomeric aggregates of the amyloidogenic proteins amyloid-β (Aβ), α-synuclein (α-syn) and tau, which are currently considered to be major targets for drug discovery in Alzheimer's disease (AD) and Parkinson's disease (PD). We show that PPE manifested a significant inhibitory effect against swelling of isolated mitochondria exposed to the amyloid oligomers, and attenuated the release of cytochrome from the mitochondria. Read More

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Suppression of aggregate and amyloid formation by a novel intrinsically disordered region in metazoan Hsp110 chaperones.

J Biol Chem 2021 Jan-Jun;296:100567. Epub 2021 Mar 19.

Department of Microbiology and Molecular Genetics, McGovern Medical School at UTHealth, Houston, Texas, USA. Electronic address:

Molecular chaperones maintain proteostasis by ensuring the proper folding of polypeptides. Loss of proteostasis has been linked to numerous neurodegenerative disorders including Alzheimer's, Parkinson's, and Huntington's disease. Hsp110 is related to the canonical Hsp70 class of protein-folding molecular chaperones and interacts with Hsp70 as a nucleotide exchange factor (NEF). Read More

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Polyphenol-Peptide Interactions in Mitigation of Alzheimer's Disease: Role of Biosurface-Induced Aggregation.

J Alzheimers Dis 2021 ;81(1):33-55

INRS-Centre Armand-Frappier Santé Biotechnologie, Laval, QC, Canada.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, responsible for nearly two-thirds of all dementia cases. In this review, we report the potential AD treatment strategies focusing on natural polyphenol molecules (green chemistry) and more specifically on the inhibition of polyphenol-induced amyloid aggregation/disaggregation pathways: in bulk and on biosurfaces. We discuss how these pathways can potentially alter the structure at the early stages of AD, hence delaying the aggregation of amyloid-β (Aβ) and tau. Read More

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January 2021

Inhibitory mechanism of an antifungal drug, caspofungin against amyloid β peptide aggregation: Repurposing via neuroinformatics and an experimental approach.

Mol Cell Neurosci 2021 04 12;112:103612. Epub 2021 Mar 12.

School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. Electronic address:

The multifactorial neurological condition called Alzheimer's disease (AD) primarily affects elderly individuals. Despite the calamitous consequences of AD, curative strategies for a regimen to apply remain inadequate as several factors contribute to AD etiology. Drug repurposing is an advance strategy prior to drug discovery as various effective drugs perform through alteration of multiple targets, and the present "poly-pharmacology" can be a curative approach to complex disorders. Read More

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Computational analysis of the effect of [Tea][Ms] and [Tea][HPO] ionic liquids on the structure and stability of Aβ(17-42) amyloid fibrils.

Phys Chem Chem Phys 2021 Mar 12;23(11):6695-6709. Epub 2021 Mar 12.

Computational and Chemical Biology, Fondazione Istituto Italiano di Tecnologia, Genova, Italy.

Experimental studies have reported the possibility of affecting the growth/dissolution of amyloid fibres by the addition of organic salts of the room-temperature ionic-liquid family, raising the tantalizing prospect of controlling these processes under physiological conditions. The effect of [Tea][Ms] and [Tea][HPO] at various concentrations on the structure and stability of a simple model of Aβ42 fibrils has been investigated by computational means. Free energy computations show that both [Tea][Ms] and [Tea][HPO] decrease the stability of fibrils with respect to isolated peptides in solution, and the effect is significantly stronger for [Tea][Ms]. Read More

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The interaction of zinc with the multi-functional plasma thyroid hormone distributor protein, transthyretin: evolutionary and cross-species comparative aspects.

Authors:
Kiyoshi Yamauchi

Biometals 2021 Jun 9;34(3):423-437. Epub 2021 Mar 9.

Department of Biological Science, Faculty of Science, Shizuoka University, Shizuoka, 422-8529, Japan.

A considerable body of evidence has been accumulated showing the interrelationship between zinc and the plasma thyroid hormone (TH) distributor protein, transthyretin (TTR). TTR is a multi-functional protein, which emerged from 5-hydroxyisourate hydrolase (HIUHase) by neo-functionalization after gene duplication during early chordate evolution. HIUHase is also a zinc-binding protein. Read More

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Structural Arrangement within a Peptide Fibril Derived from the Glaucoma-Associated Myocilin Olfactomedin Domain.

J Phys Chem B 2021 03 8;125(11):2886-2897. Epub 2021 Mar 8.

Myocilin-associated glaucoma is a new addition to the list of diseases linked to protein misfolding and amyloid formation. Single point variants of the ∼257-residue myocilin olfactomedin domain (mOLF) lead to mutant myocilin aggregation. Here, we analyze the 12-residue peptide P1 (GAVVYSGSLYFQ), corresponding to residues 326-337 of mOLF, previously shown to form amyloid fibrils and . Read More

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