Advances in protein chemistry and structural biology最新文献

Host-directed immunotherapy (HDI) is emerging as a transformative strategy in managing chronic diseases by leveraging the host's immune system to combat disease. This innovative approach has shown promise in a range of conditions, including cancer and parasitic infections. In oncology, HDI aims to enhance the body's natural immune response against cancer cells through mechanisms such as immune checkpoint inhibition, monoclonal antibodies, and cytokine therapies. These strategies are designed to boost the immune system's ability to recognize and destroy tumors, improving patient outcomes and offering alternatives to traditional cancer treatments. Similarly, in parasitic infections, HDI focuses on strengthening the host's immune defenses to control and eradicate those infections. For diseases like malaria, leishmaniasis, and Chagas disease, HDI strategies may involve adjuvants or immune modulators that amplify the body's ability to target and eliminate parasites. By optimizing immune responses and reducing reliance on conventional treatments, HDI holds the potential to revolutionize therapeutic approaches across various chronic diseases. This chapter highlights the flexibility and potential of HDI in advancing treatments, offering novel ways for improving patient care and disease management.

Neuraminidases (NAs) are glycoside hydrolase enzymes pivotal in carbohydrate metabolism, ubiquitously present in viruses, bacteria, fungi, and mammals. These enzymes catalyze the cleavage of terminal sialic acid residues from glycoproteins and glycolipids, impacting various biological processes, including pathogen infections and cancer cell proliferation. In our study, we employed advanced in silico strategies to repurpose existing drugs, aiming to provide a rapid response to health emergencies posed by multi-drug-resistant bacteria and fungi, as well as expanding the arsenal of antiviral therapies. Phylogenetic and structural superimposition analyses revealed four principal NA clusters, grouping viral, bacterial, fungal, and metazoa NAs. Comprehensive sequence and structural analyses identified three conserved binding regions across diverse species. The first binding region, observed in NAs crystallized with 23 different small molecules from viruses, fungi, bacteria, and metazoa, consists of three contact points hosting a basic RR dipeptide or RRN tripeptide, a basic/acidic R[E/D] dipeptide, and a basic/aromatic RY dipeptide involved in substrate/inhibitors binding. A second binding pocket was highlighted by comparing a group of NAs sampled from metazoa, fungi, and bacteria, crystallized in complex with 4 small molecules. The third binding pocket was proposed based on a fungal NA crystallized in complex with 1 small molecule. These identified binding pockets are proposed for being targettable by selective inhibitors of species-specific NAs, suggesting new avenues for anti-infective and anticancer strategies.

Alpha-synuclein (α-Syn) aggregation is closely linked to the pathogenesis of Parkinson's disease, where misfolded monomers form toxic oligomers and amyloid fibrils, which accumulate as Lewy bodies. Several factors, such as genetic mutations, interactions with lipids and proteins such as p62 and ubiquitin, as well as, environmental conditions, e. g. the presence of toxic metals that lead to oxidative stress. Advances in understanding the molecular mechanisms of Parkinson's disease have driven the search for novel therapies, including strategies to inhibit α-Syn aggregation and reduce its cytotoxicity consequently. Natural compounds, such as Skullcapflavone II, and synthetic ones, such 4-triazole phenylamides and phenethylamides, have demonstrated to reduce α-Syn fibrillation and aggregation. This chapter discusses the most recent therapeutic strategies in the treatment of Parkinson's disease concerning the implications of α-Syn.

This chapter focuses on how advanced computational techniques can reveal common pathways and interactions seemingly between Alzheimer's disease (AD) and breast cancer (BC). It also highlights their roles in bridging the gap between neurodegenerative and oncogenic processes by analyzing gene networks and identifying essential genes such as GAPDH, HSP90AA1, and HSPA8, which show differential regulation in AD and BC. These genes are upregulated in AD and downregulated in BC, illustrating their involvement in both disease contexts. A significant aspect of the analysis is the role of hub-bottleneck proteins within critical pathways. These hub-bottleneck proteins, including those involved in estrogen signaling, Alzheimer's disease pathways, neurodegeneration, and cancer pathways, serve as central nodes in the PPI networks. Their positioning underscores their crucial role in mediating disease mechanisms and influencing the progression of both AD and BC. The chapter emphasizes integrating gene expression data with PPI networks to uncover these critical nodes and interactions contributing to both diseases. Using network-based analysis and transcriptomics integration tools, it provides a detailed understanding of how shared genetic markers and their interactions influence disease mechanisms. This approach enables the identification of potential biomarkers and therapeutic targets by revealing underlying molecular connections and critical pathways involving hub-bottleneck proteins. The insights gained from gene overlap and PPI networks can serve as valuable input data for future studies focused on structural analysis. By laying the groundwork for understanding shared pathways and protein interactions, the research sets the stage for more detailed structural investigations and the development of precision medicine strategies tailored to the specific molecular features of Alzheimer's and breast cancer, inspiring the development of more effective treatments.

The pathophysiological scenario of Alzheimer's disease (AD) includes the misfolding and mis-sorting of two cellular proteins: Amyloid-β as plaques and microtubule-associated protein Tau as intracellular neurofibrillary tangles (NFTs). The protein oligomers are the short-lived but, highly reactive species which mediate toxicity, synaptic loss, neurodegeneration and ultimately cognitive decline. Tau oligomers can propagate through various pathway viz. the exosomal pathway, neurotransmission, cell-to-cell junction, bulk endocytosis and receptor-mediated internalization etc. The preparation, isolation and detection of oligomers were of immense importance in the current field for designing therapeutics and diagnostics. Microglia are the prime immune cells in brain which maintain the homeostasis via synaptic surveillance and tissue-remodeling. But, the senescent microglia mediate pro-inflammation, oxidative damage and phagocytosis in diseased brain. The extracellular Tau oligomers were found to interact with microglial purinergic receptor P2Y12 which then led to microglial migration, activation and phagocytosis via various remodeled actin structure. P2Y12 receptor mediates Tau oligomers-induced microglial chemotaxis by localizing with migratory actin structures such as- filopodia, lamellipodia, podosome etc. These beneficial roles of P2Y12 in microglial chemotaxis, actin remodeling and Tau clearance can be intervened as a therapeutic target in AD.

Protein misfolding is a fundamental biological process with profound implications for human health and disease. Typically, proteins assume precise three-dimensional structures to perform their functions, a process safeguarded by the proteostasis network, which comprises molecular chaperones, the ubiquitin-proteasome system (UPS), and autophagy. However, genetic mutations, oxidative stress, and environmental insults can disrupt folding, leading to the accumulation of non-functional or toxic conformations. In neurodegenerative diseases such as Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral Sclerosis (ALS), chronic misfolding results in toxic protein aggregates like amyloid-β, tau, and α-synuclein. These disrupt synaptic function, induce oxidative and nitrosative stress, and trigger apoptosis, ultimately leading to progressive neuronal loss. Dysregulation of the unfolded protein response (UPR) and weakened proteostasis with aging exacerbate disease pathology. In contrast, cancer cells utilize protein misfolding to enhance their survival and progression. Misfolded oncoproteins, such as mutant p53, not only evade degradation but also acquire oncogenic properties. Tumor cells hijack the UPR and chaperone networks, upregulate heat shock proteins, and manipulate oxidative stress responses to withstand hypoxia, nutrient deprivation, and rapid proliferation. Cancer stem cells (CSCs) further adapt to proteotoxic stress, contributing to tumor heterogeneity, therapy resistance, and immune evasion. The dual role of protein misfolding, driving degeneration in neurons while supporting proliferation in tumors, underscores its centrality in disease biology. Future research should focus on identifying early biomarkers of proteostasis imbalance and exploiting shared molecular pathways for the development of novel therapeutic interventions.

The unfolded protein response (UPR) refers to a cellular response mechanism that occurs in response to the accumulation of misfolded or incompletely folded proteins in the ER, that maintains proteostasis. While the major aim of UPR is to restrain cell homeostasis, prolonged stages results in apoptosis. The oncogenic circumstances are typically ER stressors, and UPR activation encourages the oncogenic transformation process, in which all UPR signaling branches support the development of tumors, angiogenesis, immune invasion, and resistance to chemotherapy. Proteomics is a high throughput, large-scale comprehensive study of proteins, their structures, and functions including their interactions with each other. Proteomics has now emerged as a very crucial and robust technique for biomarker discovery especially in diseases such as cancer. We summarize the use of proteomics techniques emphasizing the identification of UPR-related biomarkers by enabling the examination of protein-level alterations and modifications that propel UPR-mediated carcinogenesis. This could further be exploited for the early detection, prognosis, diagnosis and for therapeutic interventions for ER stress-mediated and UPR-mediated malignancies. This review elucidates the significant role and importance of different proteomic technologies and strategies in revealing UPR-mediated pathways in cancer, identifying main UPR effectors including GRP78, p53, PERK, IRE1α, and ATF6, and examines their potential as biomarkers for different cancer types. Integrating proteomic data with systems biology and machine learning techniques would further enhance our comprehension of UPR signaling in oncogenesis and facilitate the development of innovative tactics for personalized cancer therapy.

Alzheimer's disease is characterized by two mechanisms, one that occur extracellularly and the other occurs intracellularly. The two most important proteins are extracellular amyloid βeta (Aβ) and intracellular hyperphosphorylated Tau that are contained in senile plaques and neurofibrillary tangles respectively. AD accounts for cognitive impairment and progressive neuronal degeneration eventually, there is significant cerebral atrophy due to neuronal cell death. Initially, there is synaptic damage, synaptic loss plays a strong role in cognitive impairment in patients with AD. Also, evidence suggests that modifications in adult neurogenesis in the hippocampus plays a role in AD. It has been investigated that synaptic pathology and defective neurogenesis in AD are related to progressive accumulation of Aβ oligomers rather than fibrils. Aβ oligomer formation occurs when the APP is cleaved off and subsequently Aβ protein that is generated due to this cleavage is not cleared off by the ApoE mechanism.

Tau, an intrinsically disordered protein associated with microtubule stabilization, is crucial for cellular trafficking, and signaling pathways. Under pathological conditions, Tau undergoes post-translational modifications and structural changes, leading to its aggregation into neurofibrillary tangles (NFTs). The interactions between Tau and membrane lipids, including phospholipids like DOPC, DPPC, and proteins such as Apo E4, play a significant role in Tau aggregation. These interactions modulate Tau's structure, stabilization, and aggregation kinetics. Phospholipase C (PLC) and DEPC also influence Tau aggregation through signaling pathways and preservation of RNA integrity, respectively. Membrane lipid composition affects Tau-membrane interactions, which can promote Tau fibrillization and propagation, contributing to neurotoxicity in Alzheimer's disease (AD) and other Tauopathies. The disruption of lipid homeostasis by Apo E4, alterations in membrane fluidity and integrity by DPPC, and the influence of phospholipids on BBB functionality are significant in understanding Tau pathology.

Viral fitness presents a complex challenge that requires a deep understanding of evolution and selection pressures. The swift emergence of mutations in viruses makes them ideal models for studying evolutionary dynamics. Recent advancements in biophysical methods and structural biology have facilitated insights into how these mutations influence evolutionary trajectories at the structural level. Computationally guided structural techniques are particularly valuable for analyzing the mutational landscape across all possible mutations in viral proteins under selection pressure. The virus often interacts via the receptor binding domain (RBD) of its surface protein with the receptor protein of the host cell. This binding is a key step for the viral entry in host cell and infection. In response, the host immune response or vaccines generate antibodies to neutralize the virus particles. This creates a competitive scenario where the viral surface protein competes for binding between host cell receptor and antibodies. The viral mutations supposedly evolve to effectively bind to host receptors while evading the antibody recognition. The differential binding affinity of the viral surface protein, preferably via RBD, between host receptor and antibodies may aid in defining the molecular level viral fitness function. The present chapter explores these dynamics through the lens of severe acute respiratory syndrome coronavirus 2 spike protein, binding to human angiotensin-converting enzyme 2 and circulating antibodies. Interestingly, this strategy utilized the wealth of protein structural data from cryo-electron microscopy and biochemical data on mutations.