Fatty links between multisystem proteinopathy and Small VCP-Interacting Protein. DOI Creative Commons
Dale D. O. Martin, Firyal Ramzan, Fatima Abrar

и другие.

Research Square (Research Square), Год журнала: 2023, Номер unknown

Опубликована: Авг. 18, 2023

Abstract Multisystem proteinopathy (MSP) is a rare dominantly-inherited disorder that includes cluster of diseases, including frontotemporal dementia, inclusion body myopathy, and Paget’s disease bone. MSP caused by mutations in the gene encoding Valosin-Containing Protein (VCP). Patients with same mutation, even within family, can present different combination any or all above along amyotrophic lateral sclerosis (ALS). The pleiotropic effects may be linked to greater than 50 VCP cofactors direct VCP’s many roles cell. Small VCP-Interacting (SVIP) small protein directs autophagosomes lysosomes. We found SVIP localization an acylation-dependent manner. demonstrate myristoylated at glycine 2 palmitoylated cysteines 4 7. Acylation required mediate cell death presence MSP-associated variant (R155H-VCP), whereas blocking myristoylation prevents cytotoxicity. Therefore, acylation novel target MSP.

Язык: Английский

Mechanisms and functions of protein S-acylation DOI
Francisco S. Mesquita, Laurence Abrami, Maurine E. Linder

и другие.

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(6), С. 488 - 509

Опубликована: Фев. 14, 2024

Язык: Английский

Процитировано

50
Refining S-acylation: Structure, regulation, dynamics, and therapeutic implications DOI Creative Commons
Muhammad Anwar, Gijs R. van den Brink

The Journal of Cell Biology, Год журнала: 2023, Номер 222(11)

Опубликована: Сен. 27, 2023

With a limited number of genes, cells achieve remarkable diversity. This is to large extent achieved by chemical posttranslational modifications proteins. Amongst these are the lipid that have unique ability confer hydrophobicity. The last decade has revealed proteins extremely frequent and affect great variety cellular pathways physiological processes. particularly true for S-acylation, only reversible modification. enzymes involved in S-acylation deacylation starting be understood, list undergo this modification ever-increasing. We will describe state knowledge on regulate from their structure regulation, how influences target proteins, finally offer perspective alterations balance between may contribute disease.

Язык: Английский

Процитировано

14
Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders DOI
Jakub Włodarczyk, Raja Bhattacharyya, Kim Doré

и другие.

Journal of Neuroscience, Год журнала: 2024, Номер 44(40), С. e1225242024 - e1225242024

Опубликована: Окт. 2, 2024

Palmitoylation, a lipid-based posttranslational protein modification, plays crucial role in regulating various aspects of neuronal function through altering membrane-targeting, stabilities, and protein–protein interaction profiles. Disruption palmitoylation has recently garnered attention as disease mechanism neurodegeneration. Many proteins implicated neurodegenerative diseases associated dysfunction, including but not limited to amyloid precursor protein, β-secretase (BACE1), postsynaptic density 95, Fyn, synaptotagmin-11, mutant huntingtin, superoxide dismutase 1, undergo palmitoylation, recent evidence suggests that altered contributes the pathological characteristics these disruption cellular processes. In addition, dysfunction enzymes catalyze depalmitoylation been connected development neurological disorders. This review highlights some latest advances our understanding regulation explores potential therapeutic implications.

Язык: Английский

Процитировано

5
An S-acylated N-terminus and a conserved loop regulate the activity of the ABHD17 deacylase DOI
Sydney Holme, Jennifer Sapia, Michael Davey

и другие.

The Journal of Cell Biology, Год журнала: 2025, Номер 224(4)

Опубликована: Янв. 23, 2025

The dynamic addition and removal of long-chain fatty acids modulate protein function localization. α/β hydrolase domain-containing (ABHD) 17 enzymes remove acyl chains from membrane-localized proteins such as the oncoprotein NRas, but how ABHD17 are regulated is unknown. Here, we used cell-based studies molecular dynamics simulations to show that activity controlled by two mobile elements-an S-acylated N-terminal helix a loop-that flank putative substrate-binding pocket. Multiple S-acylation events anchor in membrane, enabling hydrophobic residues loop engage with bilayer. This stabilizes conformation both loop, alters binding pocket, optimally positions enzyme for substrate engagement. may be general feature acyl-protein thioesterases. By providing mechanistic understanding lipid modification lipid-removing promotes its enzymatic activity, this work contributes our cellular cycles.

Язык: Английский

Процитировано

0
Protein modification in neurodegenerative diseases DOI Creative Commons

Shahin Ramazi,

Maedeh Dadzadi,

Mona Darvazi

и другие.

MedComm, Год журнала: 2024, Номер 5(8)

Опубликована: Авг. 1, 2024

Abstract Posttranslational modifications play a crucial role in governing cellular functions and protein behavior. Researchers have implicated dysregulated posttranslational misfolding, which results cytotoxicity, particularly neurodegenerative diseases such as Alzheimer disease, Parkinson Huntington disease. These aberrant cause proteins to gather certain parts of the brain that are linked development diseases. This leads neuronal dysfunction start disease symptoms. Cognitive decline neurological impairments commonly manifest patients, underscoring urgency comprehending modifications’ impact on function for targeted therapeutic interventions. review elucidates critical link between specific modifications, focusing Tau, APP, α‐synuclein, Huntingtin protein, Parkin, DJ‐1, Drp1. By delineating prominent within underscores significance understanding interplay among these modifications. Emphasizing 10 key abnormal this study aims provide comprehensive framework investigating holistically. The insights presented herein shed light potential avenues aimed at modulating mitigate aggregation retard progression.

Язык: Английский

Процитировано

4
Axonal injury signaling is restrained by a spared synaptic branch DOI Open Access
Laura J. Smithson, Juliana Zang, Lucas Junginger

и другие.

Опубликована: Март 18, 2025

The intrinsic ability of injured neurons to degenerate and regenerate their axons facilitates nervous system repair, however this is not engaged in all injury locations. Here we investigate the regulation a conserved axonal response pathway with respect location damage branched motoneuron Drosophila larvae. dileucine zipper kinase DLK, (also known as MAP3K12 mammals Wallenda (Wnd) ), key regulator diverse responses injury. In three different populations motoneurons, observed same striking result that Wnd/DLK signaling becomes activated only injuries remove synaptic terminals. Injuries spare even small part terminal fail activate signaling, despite presence extensive degeneration. injury-induced occurs independently its previously regulator, Hiw/PHR ubiquitin ligase. We propose linked trafficking synapse-to-nucleus cargo mechanism enables respond impairments connectivity.

Язык: Английский

Процитировано

0
A Novel Approach to Relocate Misplaced Proteins in Cells DOI Creative Commons

Grace Hohman,

Andrew J. Watson, Mohamed A. Eldeeb

и другие.

Biology, Год журнала: 2025, Номер 14(4), С. 420 - 420

Опубликована: Апрель 14, 2025

Proper cellular function hinges on appropriate subcellular protein localization. When proteins become mislocalized, they can accumulate, cause damage, and disrupt many biochemical processes. Notably, mislocalized accumulation the resulting cytotoxic effects are salient features of neurodegenerative diseases including Alzheimer’s, Parkinson’s disease, ALS. The detrimental consequences make it crucial to develop techniques approaches that counteract this malfunction. Remarkably, a recent study by Ng et al. introduced targeted relocalization-activating molecules (TRAMs) as novel molecular tool for relocalizing endogenous target disease-associated proteins. authors developed quantitative single-cell analysis evaluate strength relocalization capability TRAMs coupling shuttle protein. Herein, we briefly highlight discuss potential implications an effective approach correcting

Язык: Английский

Процитировано

0
Oxidative Cysteine Post Translational Modifications Drive the Redox Code Underlying Neurodegeneration and Amyotrophic Lateral Sclerosis DOI Creative Commons

Anna Percio,

Michela Cicchinelli, Domiziana Masci

и другие.

Antioxidants, Год журнала: 2024, Номер 13(8), С. 883 - 883

Опубликована: Июль 23, 2024

Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, "redoxome" encompasses network redox molecules collaborating to maintain cellular balance signaling. Among these, cysteine-sensitive proteins are fundamental for homeostasis. Due their reactive thiol groups, cysteine (Cys) residues particularly susceptible oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what referred as "cysteinet" proteome, essential signaling both physiological pathological conditions, including neurodegeneration. Such significantly influence misfolding aggregation, key hallmarks diseases such Alzheimer's, Parkinson's, notably, amyotrophic lateral sclerosis (ALS). This review aims explore complex landscape PTMs environment, elucidating impact on neurodegeneration at level. By investigating specific regulatory networks involved, particular emphasis placed link dysregulation ALS, highlighting pathology a prime example disease wherein distinct hallmark.

Язык: Английский

Процитировано

3
Post-translational modifications in the Protein Data Bank DOI Creative Commons
Lucy C. Schofield, Jordan S. Dialpuri, Garib N. Murshudov

и другие.

Acta Crystallographica Section D Structural Biology, Год журнала: 2024, Номер 80(9), С. 647 - 660

Опубликована: Авг. 29, 2024

Proteins frequently undergo covalent modification at the post-translational level, which involves attachment of chemical groups onto amino acids. This can entail singular or multiple addition small groups, such as phosphorylation; long-chain modifications, glycosylation; proteins, ubiquitination; well interconversion formation pyroglutamic acid. These modifications (PTMs) are essential for normal functioning cells, they alter physicochemical properties acids and therefore influence enzymatic activity, protein localization, protein–protein interactions stability. Despite their inherent importance, accurately depicting PTMs in experimental studies structures often poses a challenge. review highlights role structures, prevalence Protein Data Bank, directing reader to built examples suitable use modelling reference.

Язык: Английский

Процитировано

3
Reduced S-acylation of SQSTM1/p62 in Huntington disease is associated with impaired autophagy DOI Open Access
Fatima Abrar, Martyn C. Davies, Ashish Kumar

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 11, 2023

Abstract Disruption of macroautophagy/autophagy has emerged as a common feature in many neurodegenerative diseases. Autophagy is membrane-dependent pathway that requires key regulators to quickly localize on and off membranes during induction promoting membrane fusion. Previously, our bioinformatic approaches have shown autophagy Huntington disease (HD) are enriched S-acylated proteins. S-acylation involves the reversible addition long chain fatty acids promote binding. Herein, we show inhibition regulates abundance several leads partial block autophagic flux. We receptor SQSTM1/p62 (sequestosome 1) directed lysosome. Importantly, see SQSTM1 significantly reduced HD patient mouse model brains, thus providing novel mechanism for generation empty autophagosomes previously seen models cells.

Язык: Английский

Процитировано

5