Recognition of the TDP-43 nuclear localization signal by importin α1/β

Cell Reports, Год журнала: 2022, Номер 39(13), С. 111007 - 111007

Опубликована: Июнь 1, 2022

Cytoplasmic mislocalization of the TAR-DNA binding protein 43 kDa (TDP-43) leads to large, insoluble aggregates that are a hallmark amyotrophic lateral sclerosis and frontotemporal dementia. Here, we study how importin α1/β recognizes TDP-43 bipartite nuclear localization signal (NLS). We find NLS makes extensive contacts with α1, especially at minor NLS-binding site. results in steric clashes C terminus α1 disrupts N-terminal domain (NTD) dimerization interface. A putative phosphorylation site proximity R83 destabilizes importins by reducing backbone dynamics. Based on these data, explain pathogenic role several post-translational modifications mutations linked disease shed light chaperone activity α1/β.

Язык: Английский

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TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury

Nature Neuroscience, Год журнала: 2022, Номер 25(12), С. 1608 - 1625

Опубликована: Ноя. 24, 2022

Язык: Английский

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Role of aberrant phase separation in pathological protein aggregation

Current Opinion in Structural Biology, Год журнала: 2023, Номер 82, С. 102678 - 102678

Опубликована: Авг. 19, 2023

Язык: Английский

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Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis

Science Advances, Год журнала: 2023, Номер 9(31)

Опубликована: Авг. 4, 2023

The cytoplasmic aggregation of TAR DNA binding protein-43 (TDP-43), also known as TDP-43 pathology, is the pathological hallmark amyotrophic lateral sclerosis (ALS). However, mechanism underlying mislocalization and subsequent remains unclear. Here, we show that dimerization/multimerization impaired in postmortem brains spinal cords patients with sporadic ALS N-terminal dimerization–deficient consists inclusion bodies motor neurons. Expression mutant Neuro2a cells induced pluripotent stem cell–derived neurons recapitulates such Nxf1-dependent aggregate formation, which induces seeding effects. Furthermore, TDP-DiLuc, a bimolecular luminescence complementation reporter assay, could detect decreased dimerization before changes caused by transcription inhibition linked to aberrant RNA metabolism ALS. These findings identified monomerization critical determinant inducing pathology

Язык: Английский

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Lost in local translation: TDP-43 and FUS in axonal/neuromuscular junction maintenance and dysregulation in amyotrophic lateral sclerosis

Neuron, Год журнала: 2023, Номер 111(9), С. 1355 - 1380

Опубликована: Март 23, 2023

Язык: Английский

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Theory and Simulation of Multiphase Coexistence in Biomolecular Mixtures

Journal of Chemical Theory and Computation, Год журнала: 2023, Номер 19(12), С. 3429 - 3445

Опубликована: Июнь 5, 2023

Biomolecular condensates constitute a newly recognized form of spatial organization in living cells. Although many are believed to as result phase separation, the physicochemical properties that determine behavior heterogeneous biomolecular mixtures only beginning be explored. Theory and simulation provide invaluable tools for probing relationship between molecular determinants, such protein RNA sequences, emergence phase-separated complex environments. This review covers recent advances prediction computational design phase-separate into coexisting phases. First, we efforts understand with hundreds or thousands species using theoretical models statistical approaches. We then describe progress developing analytical theories coarse-grained predict multiphase detail required make contact biophysical experiments. conclude by summarizing challenges ahead modeling inhomogeneous

Язык: Английский

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Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation

JACS Au, Год журнала: 2023, Номер 3(3), С. 834 - 848

Опубликована: Фев. 24, 2023

Biomolecular condensation is involved in various cellular processes; therefore, regulation of crucial to prevent deleterious protein aggregation and maintain a stable environment. Recently, class highly charged proteins, known as heat-resistant obscure (Hero) was shown protect other client proteins from pathological aggregation. However, the molecular mechanisms by which Hero remain unknown. In this study, we performed multiscale dynamics (MD) simulations Hero11, protein, C-terminal low-complexity domain (LCD) transactive response DNA-binding 43 (TDP-43), under conditions examine their interactions with each other. We found that Hero11 permeates into condensate formed LCD TDP-43 (TDP-43-LCD) induces changes conformation, intermolecular interactions, TDP-43-LCD. also examined possible structures atomistic coarse-grained MD higher fraction disordered region tends assemble on surface condensates. Based simulation results, have proposed three for Hero11's regulatory function: (i) dense phase, TDP-43-LCD reduces contact shows faster diffusion decondensation due repulsive Hero11-Hero11 interactions. (ii) dilute saturation concentration increased, its conformation relatively more extended variant, induced attractive Hero11-TDP-43-LCD (iii) small condensates can contribute avoiding fusion The provide new insights biomolecular cells conditions.

Язык: Английский

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Disrupting pathologic phase transitions in neurodegeneration

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(13)

Опубликована: Июль 2, 2023

Solid-like protein deposits found in aged and diseased human brains have revealed a relationship between insoluble accumulations the resulting deficits neurologic function. Clinically diverse neurodegenerative diseases, including Alzheimer's disease, Parkinson's frontotemporal lobar degeneration, amyotrophic lateral sclerosis, exhibit unique disease-specific biochemical signatures abnormal depositions that often correlate with disease pathogenesis. Recent evidence indicates many pathologic proteins assemble into liquid-like phases through highly coordinated process of liquid-liquid phase separation. Over last decade, biomolecular transitions emerged as fundamental mechanism cellular organization. Liquid-like condensates organize functionally related biomolecules within cell, neuropathology-associated reside these dynamic structures. Thus, examining enhances our understanding molecular mechanisms mediating toxicity across diseases. This Review explores known contributing to aberrant focusing on tau TDP-43 proteinopathies outlining potential therapeutic strategies regulate events.

Язык: Английский

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Direct prediction of intermolecular interactions driven by disordered regions

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 3, 2024

ABSTRACT Intrinsically disordered regions (IDRs) are critical for a wide variety of cellular functions, many which involve interactions with partner proteins. Molecular recognition is typically considered through the lens sequence-specific binding events. However, growing body work has shown that IDRs often interact partners in manner does not depend on precise order amino acid order, instead driven by complementary chemical leading to bound-state complexes. Despite this emerging paradigm, we lack tools describe, quantify, predict, and interpret these types structurally heterogeneous from underlying sequences. Here, repurpose physics developed originally molecular simulations develop an approach predicting intermolecular between Our enables direct prediction phase diagrams, identification chemically-specific interaction hotspots IDRs, route test mechanistic hypotheses regarding IDR function context recognition. We use our examine range systems questions highlight its versatility applicability.

Язык: Английский

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Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Янв. 22, 2024

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that characterized by the cytoplasmic mislocalization aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), other nuclear RBPs detergent-insoluble aggregates cytoplasm degenerating neurons ALS/FTD is connected to pore dysfunction defects nucleocytoplasmic transport machinery. Recent advances suggest beyond their canonical role import protein cargoes, nuclear-import receptors (NIRs) can prevent reverse TDP-43, FUS, related restore localization function. Here, we showcase NIR family how they recognize cargo, drive import, chaperone linked ALS/FTD. We also discuss promise enhancing levels developing potentiated variants as therapeutic strategies for proteinopathies.

Язык: Английский

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