Effect of gold nanoparticles on the structure and neuroprotective function of protein L-isoaspartyl methyltransferase (PIMT)

AbstractFibrillation of peptides and proteins is implicated in various neurodegenerative diseases and is a global concern. Aging leads to the formation of abnormal isoaspartate (isoAsp) residues from isomerization of normal aspartates in proteins, triggering fibril formation that leads to neurodegenerative diseases. Protein L-isoaspartyl methyltransferase (PIMT) is a repair enzyme which recognizes and converts altered isoAsp residues back to normal aspartate. Here we report the effect of gold nanoparticles (AuNPs) of different sizes on the structure and function of PIMT. Spherical AuNPs, viz. AuNS5, AuNS50 and AuNS100 (the number indicating the diameter in nm) stabilize PIMT, with AuNS100 exhibiting the best efficacy, as evident from various biophysical experiments. Isothermal titration calorimetry (ITC) revealed endothermic, but entropy driven mode of binding of PIMT with all the three AuNSs. Methyltransferase activity assay showed enhanced activity of PIMT in presence of all AuNSs, the maximum being with AuNS100. The efficacy of PIMT in presence of AuNS100 was further demonstrated by the reduction of fibrillation of Aβ42, the peptide that is implicated in Alzheimer’s disease. The enhancement of anti-fibrillation activity of PIMT with AuNS100 was confirmed from cell survival assay with PC12 derived neuronal cells against Aβ42 induced neurotoxicity.

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Influence of Ascorbic Acid on the Structure and Function of Alpha-2- macroglobulin: Investigations using Spectroscopic and Thermodynamic Techniques

Protein and Peptide Letters ◽

10.2174/0929866526666191002113525 ◽

2020 ◽

Vol 27 (3) ◽

pp. 201-209

Author(s):

Syed Saqib Ali ◽

Mohammad Khalid Zia ◽

Tooba Siddiqui ◽

Haseeb Ahsan ◽

Fahim Halim Khan

Keyword(s):

Ascorbic Acid ◽

Conformational Changes ◽

Structural Changes ◽

The Body ◽

Titration Calorimetry ◽

Spectroscopic Techniques ◽

Human Beings ◽

Plasma Ascorbic Acid ◽

Dietary Antioxidant ◽

And Function

Background: Ascorbic acid is a classic dietary antioxidant which plays an important role in the body of human beings. It is commonly found in various foods as well as taken as dietary supplement. Objective: The plasma ascorbic acid concentration may range from low, as in chronic or acute oxidative stress to high if delivered intravenously during cancer treatment. Sheep alpha-2- macroglobulin (α2M), a human α2M homologue is a large tetrameric glycoprotein of 630 kDa with antiproteinase activity, found in sheep’s blood. Methods: In the present study, the interaction of ascorbic acid with alpha-2-macroglobulin was explored in the presence of visible light by utilizing various spectroscopic techniques and isothermal titration calorimetry (ITC). Results: UV-vis and fluorescence spectroscopy suggests the formation of a complex between ascorbic acid and α2M apparent by increased absorbance and decreased fluorescence. Secondary structural changes in the α2M were investigated by CD and FT-IR spectroscopy. Our findings suggest the induction of subtle conformational changes in α2M induced by ascorbic acid. Thermodynamics signatures of ascorbic acid and α2M interaction indicate that the binding is an enthalpy-driven process. Conclusion: It is possible that ascorbic acid binds and compromises antiproteinase activity of α2M by inducing changes in the secondary structure of the protein.

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Natural Products for the Treatment of Neurodegenerative Diseases

Current Medicinal Chemistry ◽

10.2174/0929867326666190527120614 ◽

2020 ◽

Vol 27 (34) ◽

pp. 5790-5828 ◽

Cited By ~ 1

Author(s):

Ze Wang ◽

Chunyang He ◽

Jing-Shan Shi

Keyword(s):

Nervous System ◽

Natural Products ◽

Neurodegenerative Diseases ◽

Neuroprotective Effect ◽

Rapid Development ◽

New Drugs ◽

Progressive Degeneration ◽

Cord Injury ◽

The Central Nervous System ◽

And Function

Neurodegenerative diseases are a heterogeneous group of disorders characterized by the progressive degeneration of the structure and function of the central nervous system or peripheral nervous system. Alzheimer's Disease (AD), Parkinson's Disease (PD) and Spinal Cord Injury (SCI) are the common neurodegenerative diseases, which typically occur in people over the age of 60. With the rapid development of an aged society, over 60 million people worldwide are suffering from these uncurable diseases. Therefore, the search for new drugs and therapeutic methods has become an increasingly important research topic. Natural products especially those from the Traditional Chinese Medicines (TCMs), are the most important sources of drugs, and have received extensive interest among pharmacist. In this review, in order to facilitate further chemical modification of those useful natural products by pharmacists, we will bring together recent studies in single natural compound from TCMs with neuroprotective effect.

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Identification and Functional Analysis of Apoptotic Protease Activating Factor-1 (Apaf-1) from Spodoptera litura

Insects ◽

10.3390/insects12010064 ◽

2021 ◽

Vol 12 (1) ◽

pp. 64

Author(s):

Haihao Ma ◽

Xiumei Yan ◽

Lin Yan ◽

Jingyan Zhao ◽

Jiping Song ◽

...

Keyword(s):

Spodoptera Litura ◽

Actinomycin D ◽

Titration Calorimetry ◽

Apoptosis Pathway ◽

Downstream Effector ◽

Lepidopteran Insects ◽

Evolutionarily Conserved ◽

Effector Caspases ◽

And Function

Apoptotic protease activating factor-1 (Apaf-1) is an adaptor molecule, essential for activating initiator caspase and downstream effector caspases, which directly cause apoptosis. In fruit flies, nematodes, and mammals, Apaf-1 has been extensively studied. However, the structure and function of Apaf-1 in Lepidoptera remain unclear. This study identified a novel Apaf-1 from Spodoptera litura, named Sl-Apaf-1. Sl-Apaf-1 contains three domains: a CARD domain, as well as NOD and WD motifs, and is very similar to mammalian Apaf-1. Interference of Sl-apaf-1 expression in SL-1 cells blocked apoptosis induced by actinomycin D. Overexpression of Sl-apaf-1 significantly enhances apoptosis induced by actinomycin D in Sf9/SL-1/U2OS cells, suggesting that the function of Sl-Apaf-1 is evolutionarily conserved. Furthermore, Sl-Apaf-1 could interact with Sl-caspase-5 (a homologue of mammalian caspase-9) and yielded a binding affinity of 1.37 × 106 M–1 according isothermal titration calorimetry assay. Initiator caspase (procaspase-5) of S. litura could be activated by Sl-Apaf-1 (without WD motif) in vitro, and the activated Sl-caspase-5 could cleave Sl-procaspase-1 (a homologue of caspase-3 in mammals), which directly caused apoptosis. This study demonstrates the key role of Sl-Apaf-1 in the apoptosis pathway, suggesting that the apoptosis pathway in Lepidopteran insects and mammals is conserved.

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Neuroprotective Function of 14-3-3 Proteins in Neurodegeneration

BioMed Research International ◽

10.1155/2013/564534 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 45

Author(s):

Tadayuki Shimada ◽

Alyson E. Fournier ◽

Kanato Yamagata

Keyword(s):

Neurodegenerative Disease ◽

Cellular Localization ◽

Experimental Studies ◽

Adaptor Proteins ◽

Vast Number ◽

Physiological Processes ◽

Binding Partners ◽

Neuroprotective Function ◽

And Function ◽

Regulation Of Enzyme Activity

14-3-3 proteins are abundantly expressed adaptor proteins that interact with a vast number of binding partners to regulate their cellular localization and function. They regulate substrate function in a number of ways including protection from dephosphorylation, regulation of enzyme activity, formation of ternary complexes and sequestration. The diversity of 14-3-3 interacting partners thus enables 14-3-3 proteins to impact a wide variety of cellular and physiological processes. 14-3-3 proteins are broadly expressed in the brain, and clinical and experimental studies have implicated 14-3-3 proteins in neurodegenerative disease. A recurring theme is that 14-3-3 proteins play important roles in pathogenesis through regulating the subcellular localization of target proteins. Here, we review the evidence that 14-3-3 proteins regulate aspects of neurodegenerative disease with a focus on their protective roles against neurodegeneration.

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Correction: The Interplay between Protein L-Isoaspartyl Methyltransferase Activity and Insulin-Like Signaling to Extend Lifespan in Caenorhabditis elegans

PLoS ONE ◽

10.1371/annotation/d6ad8c55-fd3a-4f6c-a2ba-849e4a6500ca ◽

2013 ◽

Vol 8 (5) ◽

Author(s):

Shilpi Khare ◽

Carole L. Linster ◽

Steven G. Clarke

Keyword(s):

Caenorhabditis Elegans ◽

Methyltransferase Activity ◽

Protein L ◽

Isoaspartyl Methyltransferase

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Structural basis for recognition of human 7SK long noncoding RNA by the La-related protein Larp7

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1806276115 ◽

2018 ◽

Vol 115 (28) ◽

pp. E6457-E6466 ◽

Cited By ~ 20

Author(s):

Catherine D. Eichhorn ◽

Yuan Yang ◽

Lucas Repeta ◽

Juli Feigon

Keyword(s):

Noncoding Rna ◽

Rna Binding ◽

Rna Binding Proteins ◽

Transcription Elongation ◽

Structural Basis ◽

Titration Calorimetry ◽

Rna Recognition Motif ◽

Related Protein ◽

Binding Interface ◽

And Function

The La and the La-related protein (LARP) superfamily is a diverse class of RNA binding proteins involved in RNA processing, folding, and function. Larp7 binds to the abundant long noncoding 7SK RNA and is required for 7SK ribonucleoprotein (RNP) assembly and function. The 7SK RNP sequesters a pool of the positive transcription elongation factor b (P-TEFb) in an inactive state; on release, P-TEFb phosphorylates RNA Polymerase II to stimulate transcription elongation. Despite its essential role in transcription, limited structural information is available for the 7SK RNP, particularly for protein–RNA interactions. Larp7 contains an N-terminal La module that binds UUU-3′OH and a C-terminal atypical RNA recognition motif (xRRM) required for specific binding to 7SK and P-TEFb assembly. Deletion of the xRRM is linked to gastric cancer in humans. We report the 2.2-Å X-ray crystal structure of the human La-related protein group 7 (hLarp7) xRRM bound to the 7SK stem-loop 4, revealing a unique binding interface. Contributions of observed interactions to binding affinity were investigated by mutagenesis and isothermal titration calorimetry. NMR 13C spin relaxation data and comparison of free xRRM, RNA, and xRRM–RNA structures show that the xRRM is preordered to bind a flexible loop 4. Combining structures of the hLarp7 La module and the xRRM–7SK complex presented here, we propose a structural model for Larp7 binding to the 7SK 3′ end and mechanism for 7SK RNP assembly. This work provides insight into how this domain contributes to 7SK recognition and assembly of the core 7SK RNP.

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Mitochondrial Quality Control and Restraining Innate Immunity

Annual Review of Cell and Developmental Biology ◽

10.1146/annurev-cellbio-021820-101354 ◽

2020 ◽

Vol 36 (1) ◽

pp. 265-289

Author(s):

Andrew T. Moehlman ◽

Richard J. Youle

Keyword(s):

Innate Immunity ◽

Quality Control ◽

Neurodegenerative Diseases ◽

Innate Immune ◽

Interferon Response ◽

Mitochondrial Quality Control ◽

Selective Autophagy ◽

Eukaryotic Organisms ◽

And Function

Maintaining mitochondrial health is essential for the survival and function of eukaryotic organisms. Misfunctioning mitochondria activate stress-responsive pathways to restore mitochondrial network homeostasis, remove damaged or toxic proteins, and eliminate damaged organelles via selective autophagy of mitochondria, a process termed mitophagy. Failure of these quality control pathways is implicated in the pathogenesis of Parkinson's disease and other neurodegenerative diseases. Impairment of mitochondrial quality control has been demonstrated to activate innate immune pathways, including inflammasome-mediated signaling and the antiviral cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)–regulated interferon response. Immune system malfunction is a common hallmark in many neurodegenerative diseases; however, whether inflammation suppresses or exacerbates disease pathology is still unclear. The goal of this review is to provide a historical overview of the field, describe mechanisms of mitochondrial quality control, and highlight recent advances on the emerging role of mitochondria in innate immunity and inflammation.

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Multivalent Lactose–Ferrocene Conjugates Based on Poly (Amido Amine) Dendrimers and Gold Nanoparticles as Electrochemical Probes for Sensing Galectin-3

Nanomaterials ◽

10.3390/nano10020203 ◽

2020 ◽

Vol 10 (2) ◽

pp. 203 ◽

Cited By ~ 2

Author(s):

Manuel C. Martos-Maldonado ◽

Indalecio Quesada-Soriano ◽

Luis García-Fuentes ◽

Antonio Vargas-Berenguel

Keyword(s):

Gold Nanoparticles ◽

Surface Modification ◽

Cardiac Remodeling ◽

Building Blocks ◽

Differential Pulse ◽

Pamam Dendrimers ◽

Titration Calorimetry ◽

Vis Spectroscopy ◽

Galectin 3 ◽

Pulse Voltammetry

Galectin-3 is considered a cancer biomarker and bioindicator of fibrosis and cardiac remodeling and, therefore, it is desirable to develop convenient methods for its detection. Herein, an approach based on the development of multivalent electrochemical probes with high galectin-3 sensing abilities is reported. The probes consist of multivalent presentations of lactose–ferrocene conjugates scaffolded on poly (amido amine) (PAMAM) dendrimers and gold nanoparticles. Such multivalent lactose–ferrocene conjugates are synthesized by coupling of azidomethyl ferrocene–lactose building blocks on alkyne-functionalized PAMAM, for the case of the glycodendrimers, and to disulfide-functionalized linkers that are then used for the surface modification of citrate-stabilized gold nanoparticles. The binding and sensing abilities toward galectin-3 of both ferrocene-containing lactose dendrimers and gold nanoparticles have been evaluated by means of isothermal titration calorimetry, UV–vis spectroscopy, and differential pulse voltammetry. The highest sensitivity by electrochemical methods to galectin-3 was shown by lactosylferrocenylated gold nanoparticles, which are able to detect the lectin in nanomolar concentrations.

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Regulatory Roles of Bone in Neurodegenerative Diseases

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.610581 ◽

2020 ◽

Vol 12 ◽

Author(s):

Zhengran Yu ◽

Zemin Ling ◽

Lin Lu ◽

Jin Zhao ◽

Xiang Chen ◽

...

Keyword(s):

Stem Cells ◽

Neurodegenerative Diseases ◽

The Elderly ◽

Lymphoid Organ ◽

The Body ◽

Hematopoietic Stem ◽

Brain Functions ◽

And Function ◽

The Impact ◽

The Brain

Osteoporosis and neurodegenerative diseases are two kinds of common disorders of the elderly, which often co-occur. Previous studies have shown the skeletal and central nervous systems are closely related to pathophysiology. As the main structural scaffold of the body, the bone is also a reservoir for stem cells, a primary lymphoid organ, and an important endocrine organ. It can interact with the brain through various bone-derived cells, mostly the mesenchymal and hematopoietic stem cells (HSCs). The bone marrow is also a place for generating immune cells, which could greatly influence brain functions. Finally, the proteins secreted by bones (osteokines) also play important roles in the growth and function of the brain. This article reviews the latest research studying the impact of bone-derived cells, bone-controlled immune system, and bone-secreted proteins on the brain, and evaluates how these factors are implicated in the progress of neurodegenerative diseases and their potential use in the diagnosis and treatment of these diseases.

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