Intrinsically Disordered Proteins: An Overview

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(22), С. 14050 - 14050

Опубликована: Ноя. 14, 2022

Many proteins and protein segments cannot attain a single stable three-dimensional structure under physiological conditions; instead, they adopt multiple interconverting conformational states. Such intrinsically disordered or are highly abundant across proteomes, involved in various effector functions. This review focuses on different aspects of regions, which form the basis so-called “Disorder–function paradigm” proteins. Additionally, experimental approaches computational tools used for characterizing regions discussed. Finally, role diseases their utility as potential drug targets explored.

Язык: Английский

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Lipids uniquely alter the secondary structure and toxicity of amyloid beta 1–42 aggregates

FEBS Journal, Год журнала: 2023, Номер 290(12), С. 3203 - 3220

Опубликована: Янв. 27, 2023

Abrupt aggregation of amyloid β

Язык: Английский

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Protein amyloid aggregate: Structure and function

Aggregate, Год журнала: 2023, Номер 4(4)

Опубликована: Март 10, 2023

Abstract Protein amyloid aggregation has been widely observed to occur and plays important roles in both physiological processes pathological diseases. Remarkably, aggregates assembled by native proteins gain a variety of different biological activities, which cannot be adopted the unassembled protein alone. Thus, it is investigate molecular basis self‐assembly how aggregated structure determines its function. In review, we firstly introduce our structural knowledge on undergo conformational transition assemble into aggregate, with main focus fibril, major species aggregate. Then, elaborate structures fibrils enable them fulfill highly diverse functions either or condition. Furthermore, discuss polymorph very unique feature implication understanding structure‐function relationship fibrils. Finally, point out importance applying integrating new approaches for deepening study highlight potential designing fibril‐based functional bio‐nanomaterials application.

Язык: Английский

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Amyloid aggregates exert cell toxicity causing irreversible damages in the endoplasmic reticulum

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2022, Номер 1868(11), С. 166485 - 166485

Опубликована: Июль 13, 2022

Amyloid oligomers and fibrils are protein aggregates that cause an onset progression of many neurodegenerative diseases, diabetes type 2 systemic amyloidosis. Although a growing body evidence shows trigger mitochondrial dysfunction simultaneously enhancing production reactive oxygen species, exact mechanisms by which these exert their toxicities remain unclear. In this study, we used advanced microscopic spectroscopic methods to examine topography structure insulin grown in the lipid-free environment, as well presence major classes phospho- sphingolipids. We also employed set molecular markers determine extent induce damage cell endoplasmic reticulum (ER), important organelle for calcium storage, synthesis folding. Our results show activate expression Activating Transcription Factor 6 (ATF6), transmembrane is involved unfolded response (UPR) stressed ER. At same time, two other ER proteins, Inositol Requiring 1 (IRE1α) eLF2a, product PKR-like kinase (PERK), exhibited very low levels. Furthermore, amyloid 78-kDa glucose-regulated GRP78, UPR. observed UPR-induced proapoptotic transcription factor CHOP, which, turn, regulates caspase 3 BCL2 family members, including localized Bax. These findings UPR-associated stress ultimately fatal changes homeostasis.

Язык: Английский

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Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID

Journal of Personalized Medicine, Год журнала: 2024, Номер 14(2), С. 170 - 170

Опубликована: Янв. 31, 2024

Postural orthostatic tachycardia syndrome (POTS) is a common accompaniment of variety chronic, inflammatory diseases, including long COVID, as are small, insoluble, 'fibrinaloid' microclots. We here develop the argument, with accompanying evidence, that fibrinaloid microclots, through their ability to block flow blood microcapillaries and thus cause tissue hypoxia, not simply correlated but in fact, by preceding it, may be chief intermediary POTS, which body's exaggerated 'physiological' response hypoxia. Similar reasoning accounts for symptoms bundled under term 'fatigue'. Amyloids known membrane disruptors, when targets nerve membranes, this can explain neurotoxicity hence autonomic nervous system dysfunction contributes POTS. Taken together view, we indicate microclots serve link POTS fatigue COVID manner at once both mechanistic explanatory. This has clear implications treatment such diseases.

Язык: Английский

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AmyP53 Prevents the Formation of Neurotoxic β-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides: Insights for Alzheimer’s Disease Therapy

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(2), С. 1760 - 1760

Опубликована: Янв. 16, 2023

A broad range of data identify Ca2+-permeable amyloid pores as the most neurotoxic species Alzheimer's β-amyloid peptide (Aβ1-42). Following failures clinical trials targeting plaques by immunotherapy, a consensus is gradually emerging to change paradigm, strategy, and target cure disease. In this context, therapeutic AmyP53 was designed prevent pore formation driven lipid raft microdomains plasma membrane. Here, we show that outcompetes Aβ1-42 binding rafts through unique mode interaction with gangliosides. Using combination cellular, physicochemical, in silico approaches, unraveled mechanism action at atomic, molecular, cellular levels. Molecular dynamics simulations (MDS) indicated rapidly adapts its conformation gangliosides for an optimal periphery raft, where occurs. Hence, define it adaptive peptide. Our results describe first time kinetics atomic level. Physicochemical studies cannot interact presence AmyP53. These demonstrated prevents Ca2+ entry competitive inhibition The molecular details revealed unprecedent rafts, offering innovative opportunities ganglioside-associated diseases, including Alzheimer's, Parkinson's, related proteinopathies.

Язык: Английский

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Elucidation of molecular mechanisms by which amyloid β1–42 fibrils exert cell toxicity

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Год журнала: 2024, Номер 1869(6), С. 159510 - 159510

Опубликована: Май 15, 2024

Язык: Английский

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Preclinical assessment of a ganglioside-targeted therapy for Parkinson’s disease with the first-in-class adaptive peptide AmyP53

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 17, 2025

We propose a new concept for the treatment of Parkinson's disease (PD), which considers that its root cause, α-synuclein, is an intrinsically disordered protein (IDP) difficult to target by classic approaches. Upon binding lipid raft gangliosides, α-synuclein shifts from random coil α-helix, forming Ca2+-permeable oligomeric pores triggering neurotoxicity cascade. used α-synuclein-ganglioside interaction as guideline design therapeutic peptide (AmyP53) combines respective flexible ganglioside-binding domains and Alzheimer's β-amyloid protein. AmyP53 adaptive peptide, first representant class. It acts competitive inhibitor oligomer formation in brain cell membranes prevents subsequent downstream synaptotoxicity, including loss dopaminergic neurons animal injection model PD. active against both wild-type mutant forms α-synuclein. administered intranasally without side effects. This "target (gangliosides), not arrow (IDP)" distinct centric approaches did cure PD so far.

Язык: Английский

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Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions

The Journal of Physical Chemistry B, Год журнала: 2022, Номер 126(49), С. 10317 - 10326

Опубликована: Дек. 5, 2022

Understanding the atomistic resolution changes during self-assembly of amyloid peptides or proteins is important to develop compounds conditions alter aggregation pathways and suppress toxicity potentially aid in development drugs. However, complexity protein transient order/disorder oligomers along fibril are very challenging. In this Perspective, we discuss computational studies polypeptides carried out under various conditions, including closely mimicking vivo point challenges obtaining physiologically relevant results, focusing mainly on amyloid-beta Aβ peptides.

Язык: Английский

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Exploring the Application Potential of α-Synuclein Molecular Probes in Early Diagnosis of Parkinson’s Disease: Focus on Imaging Methods

ACS Chemical Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Май 7, 2025

This review aims to explore the potential application of α-synuclein (α-syn) molecular probes in early diagnosis Parkinson's disease (PD), particularly through systematic evaluation using medical imaging methods. In recent years, The abnormal aggregation α-syn within central nervous system is now recognized as a driver PD pathophysiology, solidifying its role critical diagnostic and prognostic biomarker. Early for enabling precision therapeutic interventions mitigating neurodegenerative progression, thereby enhancing long-term functional outcomes quality life. However, challenges remain clinical practice, concerning late timing lack specific biomarkers. By analyzing existing literature, we will assess effectiveness different techniques combined with discuss their advantages limitations applications. These methods can provide visualization pathological changes, helping improve recognition rate PD. Finally, emphasize importance future research new technologies that rates treatment

Язык: Английский

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