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The Journal of Physical Chemistry. B Jun 2024In recent work we proposed that interdiction in the earliest contact-formation events along the folding pathway of key viral proteins could provide a novel avenue for... (Review)
Review
A Perspective on Interdicting in Protein Misfolding for Therapeutic Drug Design: Modulating the Formation of Nonlocal Contacts in α-Synuclein as a Strategy against Parkinson's Disease.
In recent work we proposed that interdiction in the earliest contact-formation events along the folding pathway of key viral proteins could provide a novel avenue for therapeutic drug design. In this Perspective we explore the potential applicability of the protein folding interdiction strategy in the realm of neurodegenerative diseases with a specific focus on synucleinopathies. In order to fulfill this goal we review the interdiction proposal and its practical challenges, and we present new results concerning design strategies for possible peptide drugs that could be useful in preventing α-synuclein aggregation.
PubMed: 38940731
DOI: 10.1021/acs.jpcb.3c07519 -
Frontiers in Bioscience (Landmark... Jun 2024
Topics: Humans; Biomarkers; Dementia; Proteostasis Deficiencies; Protein Folding; Alzheimer Disease
PubMed: 38940055
DOI: 10.31083/j.fbl2906227 -
Frontiers in Bioscience (Landmark... Jun 2024The endoplasmic reticulum (ER) played an important role in the folding, assembly and post-translational modification of proteins. ER homeostasis could be disrupted by... (Review)
Review
The endoplasmic reticulum (ER) played an important role in the folding, assembly and post-translational modification of proteins. ER homeostasis could be disrupted by the accumulation of misfolded proteins, elevated reactive oxygen species (ROS) levels, and abnormal Ca2+ signaling, which was referred to ER stress (ERS). Ferroptosis was a unique programmed cell death model mediated by iron-dependent phospholipid peroxidation and multiple signaling pathways. The changes of mitochondrial structure, the damage of glutathione peroxidase 4 (GPX4) and excess accumulation of iron were the main characteristics of ferroptosis. ROS produced by ferroptosis can interfere with the activity of protein-folding enzymes, leading to the accumulation of large amounts of unfolded proteins, thus causing ERS. On the contrary, the increase of ERS level could promote ferroptosis by the accumulation of iron ion and lipid peroxide, the up-regulation of ferroptosis related genes. At present, the studies on the relationship between ferroptosis and ERS were one-sided and lack of in-depth studies on the interaction mechanism. This review aimed to explore the molecular mechanism of cross-talk between ferroptosis and ERS, and provide new strategies and targets for the treatment of liver diseases.
Topics: Ferroptosis; Humans; Endoplasmic Reticulum Stress; Liver Diseases; Reactive Oxygen Species; Animals; Signal Transduction; Iron; Lipid Peroxidation; Endoplasmic Reticulum
PubMed: 38940044
DOI: 10.31083/j.fbl2906221 -
Journal of Biomedical Science Jun 2024The endoplasmic reticulum (ER) employs stringent quality control mechanisms to ensure the integrity of protein folding, allowing only properly folded, processed and... (Review)
Review
The endoplasmic reticulum (ER) employs stringent quality control mechanisms to ensure the integrity of protein folding, allowing only properly folded, processed and assembled proteins to exit the ER and reach their functional destinations. Mutant proteins unable to attain their correct tertiary conformation or form complexes with their partners are retained in the ER and subsequently degraded through ER-associated protein degradation (ERAD) and associated mechanisms. ER retention contributes to a spectrum of monogenic diseases with diverse modes of inheritance and molecular mechanisms. In autosomal dominant diseases, when mutant proteins get retained in the ER, they can interact with their wild-type counterparts. This interaction may lead to the formation of mixed dimers or aberrant complexes, disrupting their normal trafficking and function in a dominant-negative manner. The combination of ER retention and dominant-negative effects has been frequently documented to cause a significant loss of functional proteins, thereby exacerbating disease severity. This review aims to examine existing literature and provide insights into the impact of dominant-negative effects exerted by mutant proteins retained in the ER in a range of autosomal dominant diseases including skeletal and connective tissue disorders, vascular disorders, neurological disorders, eye disorders and serpinopathies. Most crucially, we aim to emphasize the importance of this area of research, offering substantial potential for understanding the factors influencing phenotypic variability associated with genetic variants. Furthermore, we highlight current and prospective therapeutic approaches targeted at ameliorating the effects of mutations exhibiting dominant-negative effects. These approaches encompass experimental studies exploring treatments and their translation into clinical practice.
Topics: Humans; Endoplasmic Reticulum; Genes, Dominant; Endoplasmic Reticulum-Associated Degradation; Protein Folding; Mutation
PubMed: 38937821
DOI: 10.1186/s12929-024-01054-1 -
EMBO Reports Jun 2024Hsp90 is a molecular chaperone that acts on its clients through an ATP-dependent and conformationally dynamic functional cycle. The cochaperone Accelerator of Hsp90...
Hsp90 is a molecular chaperone that acts on its clients through an ATP-dependent and conformationally dynamic functional cycle. The cochaperone Accelerator of Hsp90 ATPase, or Ahsa1, is the most potent stimulator of Hsp90 ATPase activity. Ahsa1 stimulates the rate of Hsp90 ATPase activity through a conserved motif, NxNNWHW. Metazoan Ahsa1, but not yeast, possesses an additional 20 amino acid peptide preceding the NxNNWHW motif that we have called the intrinsic chaperone domain (ICD). The ICD of Ahsa1 diminishes Hsp90 ATPase stimulation by interfering with the function of the NxNNWHW motif. Furthermore, the NxNNWHW modulates Hsp90's apparent affinity to Ahsa1 and ATP. Lastly, the ICD controls the regulated recruitment of Hsp90 in cells and its deletion results in the loss of interaction with Hsp90 and the glucocorticoid receptor. This work provides clues to how Ahsa1 conserved regions modulate Hsp90 kinetics and how they may be coupled to client folding status.
PubMed: 38937628
DOI: 10.1038/s44319-024-00193-8 -
Journal of Molecular Biology Jun 2024Assessing membrane protein stability is among the major challenges in protein science due to their inherent complexity, which complicates the application of conventional...
The structural stability of membrane proteins revisited: Combined thermodynamic and spectral phasor analysis of SDS-induced denaturation of a thermophilic Cu(I)-transport ATPase.
Assessing membrane protein stability is among the major challenges in protein science due to their inherent complexity, which complicates the application of conventional biophysical tools. In this work, sodium dodecyl sulfate-induced denaturation of AfCopA, a Cu(I)-transport ATPase from Archaeoglobus fulgidus, was explored using a combined model-free spectral phasor analysis and a model-dependent thermodynamic analysis. Decrease in tryptophan and 1-anilino-naphthalene-8-sulfonate fluorescence intensity, displacements in the spectral phasor space, and the loss of ATPase activity were reversibly induced by this detergent. Refolding from the SDS-induced denatured state yields an active enzyme that is functionally and spectroscopically indistinguishable from the native state of the protein. Phasor analysis of Trp spectra allowed us to identify two intermediate states in the SDS-induced denaturation of AfCopA, a result further supported by principal component analysis. In contrast, traditional thermodynamic analysis detected only one intermediate state, and including the second one led to overparameterization. Additionally, ANS fluorescence spectral analysis detected one more intermediate and a gradual change at the level of the hydrophobic transmembrane surface of the protein. Based on this evidence, a model for acquiring the native structure of AfCopA in a membrane-like environment is proposed.
PubMed: 38936696
DOI: 10.1016/j.jmb.2024.168689 -
Molecular Diversity Jun 2024The development of anti-AD drugs has attracted much attention as the number of AD patients is increasing year by year. Five diosmetin derivatives (1-5) were designed and...
The development of anti-AD drugs has attracted much attention as the number of AD patients is increasing year by year. Five diosmetin derivatives (1-5) were designed and synthesized by introducing carbamate groups. The crystal structure of 1 was analyzed by X-ray diffraction, which showed a large conjugated coplanar structure and might be favorable for the insertion into the Aβ folding. Meanwhile, in vitro experiments were carried out to investigate the anticholinesterase activity, metal chelating property, antioxidant activity, and anti-Aβ aggregation ability of 1-5. The results showed that 1-5 had good cholinesterase inhibitory activities. Compound 4 showed the highest inhibitory activities against butyrylcholinesterase (IC = 0.0760 μM). Further kinetic experiments and molecular docking studies showed that 4 could bind well to butyrylcholinesterase. The molecular dynamics simulations also signified that compared with diosmetin, 4 could reduce the flexibility of the butyrylcholinesterase protein skeleton to a greater extent, and thus had a better inhibitory effect. In addition, 1-5 could selectively chelate copper ions and all of them had good antioxidant activity as well as anti-Aβ aggregation ability. Among them, 4 had the strongest activity to inhibit Cu-induced Aβ aggregation (51.09%) and had low cytotoxicity. In addition, in vivo ROS activity assay (Caenorhabditis elegans) showed that 4 had the ability to scavenge ROS. Besides, the in vivo Aβ aggregation assay showed that 4 could reduce Aβ aggregation. In conclusion, 4 has the potential to be developed into a multifunctional anti-AD drug.
PubMed: 38935304
DOI: 10.1007/s11030-024-10913-w -
Molecules (Basel, Switzerland) Jun 2024Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer's. Current drug discovery efforts have focused on molecules with tau fibril...
Exploring Tau Fibril-Disaggregating and Antioxidating Molecules Binding to Membrane-Bound Amyloid Oligomers Using Machine Learning-Enhanced Docking and Molecular Dynamics.
Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer's. Current drug discovery efforts have focused on molecules with tau fibril disaggregation and antioxidation functions. However, recent studies suggest that membrane-bound tau-containing oligomers (mTCOs), smaller and less ordered than tau fibrils, are neurotoxic in the early stage of Alzheimer's. Whether tau fibril-targeting molecules are effective against mTCOs is unknown. The binding of epigallocatechin-3-gallate (EGCG), CNS-11, and BHT-CNS-11 to in silico mTCOs and experimental tau fibrils was investigated using machine learning-enhanced docking and molecular dynamics simulations. EGCG and CNS-11 have tau fibril disaggregation functions, while the proposed BHT-CNS-11 has potential tau fibril disaggregation and antioxidation functions like EGCG. Our results suggest that the three molecules studied may also bind to mTCOs. The predicted binding probability of EGCG to mTCOs increases with the protein aggregate size. In contrast, the predicted probability of CNS-11 and BHT-CNS-11 binding to the dimeric mTCOs is higher than binding to the tetrameric mTCOs for the homo tau but not for the hetero tau-amylin oligomers. Our results also support the idea that anionic lipids may promote the binding of molecules to mTCOs. We conclude that tau fibril-disaggregating and antioxidating molecules may bind to mTCOs, and that mTCOs may also be useful targets for Alzheimer's drug design.
Topics: tau Proteins; Molecular Dynamics Simulation; Machine Learning; Molecular Docking Simulation; Humans; Protein Binding; Antioxidants; Amyloid; Catechin; Protein Aggregates
PubMed: 38930883
DOI: 10.3390/molecules29122818 -
Molecules (Basel, Switzerland) Jun 2024Galectin-3 is a protein involved in many intra- and extra-cellular processes. It has been identified as a diagnostic or prognostic biomarker for certain types of heart...
Galectin-3 is a protein involved in many intra- and extra-cellular processes. It has been identified as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease and cancer. Galectin-3 comprises a carbohydrate recognition domain (CRD) and an N-terminal domain (NTD), which is unstructured and contains eight collagen-like Pro-Gly-rich tandem repeats. While the structure of the CRD has been solved using protein crystallography, current knowledge about conformations of full-length galectin-3 is limited. To fill in this knowledge gap, we performed molecular dynamics (MD) simulations of full-length galectin-3. We systematically re-scaled the solute-solvent interactions in the Martini 3 force field to obtain the best possible agreement between available data from SAXS experiments and the ensemble of conformations generated in the MD simulations. The simulation conformations were found to be very diverse, as reflected, e.g., by (i) large fluctuations in the radius of gyration, ranging from about 2 to 5 nm, and (ii) multiple transient contacts made by amino acid residues in the NTD. Consistent with evidence from NMR experiments, contacts between the CRD and NTD were observed to not involve the carbohydrate-binding site on the CRD surface. Contacts within the NTD were found to be made most frequently by aromatic residues. Formation of fuzzy complexes with unspecific stoichiometry was observed to be mediated mostly by the NTD. Taken together, we offer a detailed picture of the conformational ensemble of full-length galectin-3, which will be important for explaining the biological functions of this protein at the molecular level.
Topics: Molecular Dynamics Simulation; Humans; Galectin 3; Protein Conformation; Galectins; Protein Folding; Protein Binding; Binding Sites; Blood Proteins
PubMed: 38930833
DOI: 10.3390/molecules29122768 -
International Journal of Molecular... Jun 2024Heat stroke, a hazardous hyperthermia-related illness, is characterized by CNS injury, particularly long-lasting brain damage. A root cause for hyperthermic neurological...
Heat stroke, a hazardous hyperthermia-related illness, is characterized by CNS injury, particularly long-lasting brain damage. A root cause for hyperthermic neurological damage is heat-induced proteotoxic stress through protein aggregation, a known causative agent of neurological disorders. Stress magnitude and enduring persistence are highly correlated with hyperthermia-associated neurological damage. We used an untargeted proteomic approach using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify and characterize time-series proteome-wide changes in dose-responsive proteotoxic stress models in medulloblastoma [Daoy], neuroblastoma [SH-SY5Y], and differentiated SH-SY5Y neuron-like cells [SH(D)]. An integrated analysis of condition-time datasets identified global proteome-wide differentially expressed proteins (DEPs) as part of the heat-induced proteotoxic stress response. The condition-specific analysis detected higher DEPs and upregulated proteins in extreme heat stress with a relatively conservative and tight regulation in differentiated SH-SY5Y neuron-like cells. Functional network analysis using ingenuity pathway analysis (IPA) identified common intercellular pathways associated with the biological processes of protein, RNA, and amino acid metabolism and cellular response to stress and membrane trafficking. The condition-wise temporal pathway analysis in the differentiated neuron-like cells detects a significant pathway, functional, and disease association of DEPs with processes like protein folding and protein synthesis, Nervous System Development and Function, and Neurological Disease. An elaborate dose-dependent stress-specific and neuroprotective cellular signaling cascade is also significantly activated. Thus, our study provides a comprehensive map of the heat-induced proteotoxic stress response associating proteome-wide changes with altered biological processes. This helps to expand our understanding of the molecular basis of the heat-induced proteotoxic stress response with potential translational connotations.
Topics: Humans; Neurons; Proteomics; Proteome; Cell Line, Tumor; Heat-Shock Response; Tandem Mass Spectrometry; Chromatography, Liquid; Cell Differentiation; Proteotoxic Stress
PubMed: 38928492
DOI: 10.3390/ijms25126787