Advances in protein chemistry and structural biology最新文献

Histones are positively charged proteins found in the chromatin of eukaryotic cells. They regulate gene expression and are required for the organization and packaging of DNA within the nucleus. Histones are extremely conserved, allowing for transcription, replication, and repair. This review delves into their complex structure and function in DNA assembly, their role in nucleosome assembly, and the higher-order chromatin structures they generate. We look at the five different types of histone proteins: H1, H2A, H2B, H3, H4, and their variations. These histones bind with DNA to produce nucleosomes, the basic units of chromatin that are essential for compacting DNA and controlling its accessibility. Their dynamic control of chromatin accessibility has important implications for genomic stability and cellular activities. We elucidate regulatory mechanisms in both normal and pathological situations by investigating their structural features, diverse interaction mechanisms, and chromatin impact. In addition, we discuss the functions of histone post-translational modifications (PTMs) and their significance in various disorders. These alterations, which include methylation, acetylation, phosphorylation, and ubiquitination, are crucial in regulating histone function and chromatin dynamics. We specifically describe and explore the role of changed histones in the evolution of cancer, neurological disorders, sepsis, autoimmune illnesses, and inflammatory conditions. This comprehensive review emphasizes histone's critical role in genomic integrity and their potential as therapeutic targets in various diseases.

The nuclear envelope has for long been considered more than just the physical border between the nucleoplasm and the cytoplasm, emerging as a crucial player in genome organisation and regulation within the 3D nucleus. Consequently, its study has become a valuable topic in the research of cancer, ageing and several other diseases where chromatin organisation is compromised. In this chapter, we will delve into its several sub-elements, such as the nuclear lamina, nuclear pore complexes and nuclear envelope proteins, and their diverse roles in nuclear function and maintenance. We will explore their functions beyond nuclear structure and transport focusing on their interactions with chromatin and their paramount influence in its organisation, regulation and expression at the nuclear periphery. Finally, we will outline how this chromatin organisation and regulation at the nuclear envelope is affected in diseases, including laminopathies, cancer, neurodegenerative diseases and during viral infections.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks hormone receptors, which makes it more likely to metastasize and have a poor prognosis. Despite some effectiveness of chemotherapy, TNBC remains challenging to manage, with high relapse and mortality rates. Recent findings have highlighted the role of the ubiquitin-protease system in TNBC, with ABI2 identified as a significant regulator. Reduced ABI2 expression is associated with aggressive disease and poor outcomes, whereas ABI2 overexpression (OE-ABI2) inhibits TNBC cell proliferation by modulating the PI3K/Akt signaling pathway. Although ABI2 is not a nuclear protein, it influences critical nuclear functions such as DNA repair and gene expression. Nuclear proteins, particularly those in the nuclear pore complex and nuclear matrix, are essential for cellular functions and have been linked to various diseases, including cancer. This study used RNA sequencing (RNA-seq) to examine the gene expression in MDA-MB-231 cell line and ABI2-overexpressing cells. Differentially expressed genes were annotated, and a protein-protein interaction network was constructed. Network and enrichment analysis identified the nucleoporins NUP54 and NUP153 as potential novel targets for TNBC. This study emphasizes the impact of ABI2 on nuclear proteins and suggests that targeting NUP54 and NUP153 could offer new therapeutic options for TNBC.

High-mobility group box 1 (HMGB1) is a highly conserved nuclear protein involved in key nuclear processes such as DNA repair, replication, and gene regulation. Beyond its established nuclear roles, HMGB1 has crucial functions in the cytoplasm and extracellular environment. When translocated to the cytoplasm, HMGB1 plays a role in autophagy, cell survival, and immune response modulation. In its extracellular form, HMGB1 acts as a damage-associated molecular pattern molecule, initiating inflammatory responses by interacting with receptors such as Receptor for advanced glycation endproducts and Toll-like receptors. Recent studies have shown its role in promoting tissue regeneration, wound healing, and angiogenesis, highlighting its dual role in both inflammation and tissue repair. Notably, the redox status of HMGB1 influences its function, with the reduced form promoting autophagy and the disulfide form driving inflammation. Dysregulation of HMGB1 contributes to the progression of various diseases, including cancer, where it influences tumor growth, metastasis, and resistance to therapy. This review provides an overview of the nuclear, cytoplasmic, and extracellular roles of HMGB1, discussing its involvement in nuclear homeostasis, rare genetic diseases, autophagy, inflammation, cancer progression, and tissue regeneration.

Over the years, extensive research has been dedicated to performing in-depth analysis of cancer to uncover the intricate details of its nature - including the types of cancer, causative agents, stimulators of disease progression, factors contributing to poor prognosis, and efficient therapies to restrict the metastatic aggressiveness. This chapter highlights the mechanisms through which different arms of the host immune system - namely cytokines, lymphocytes, antigen-presenting cells (APCs) -can be mobilized to eradicate cancer. Most malignant tumors are either poorly immunogenic, or are harbored in a highly immuno-suppressive microenvironment. This is why reinforcing the host's anti-tumor defenses, through infusion of pro-inflammatory cytokines, tumor antigen-loaded APCs, and anti-tumor cytotoxic cells has emerged as a viable treatment option against cancer. The chapter also highlights the ongoing preclinical and clinical studies in different malignancies and the outcome of various therapies. Although these methods are not foolproof, and antigen escape variants can still evade or develop resistance to customized therapies, they achieve disease stabilization in several cases when conventional treatments fail. In many instances, combination therapies involving cytokines, T cells, and vaccinations prove more effective than monotherapies. The limitations of the current therapies are also discussed, along with ongoing modifications aimed at improving efficacy.

Lipids play an essential role in synaptic function, significantly impacting synaptic physiology through their dynamic nature and signaling capabilities. Membrane lipids, including cholesterol, phospholipids, and gangliosides, are crucial for synaptic organization and function. They act as structural integrators and signaling molecules, guiding vesicle intracellular movement and regulating enzyme activity to support neuronal activity. The lipid compositions of pre-synaptic and post-synaptic membranes influence vesicle generation and receptor mobility, highlighting their active involvement in synaptic processes. Astrocytes also contribute to synaptic health by upholding the blood-brain barrier, regulating ion levels, and providing metabolic support. Lipid-mediated processes control synaptic plasticity and development, with astrocytes playing a crucial role in glutamate homeostasis. Amyloid-beta and Tau proteins are key in Alzheimer's disease (AD), where synaptic disruption leads to cognitive deficits. Clathrin-mediated endocytosis (CME) and caveolin-mediated endocytosis are critical pathways for lipid-mediated synaptic function, with disruptions in these pathways contributing to AD pathogenesis.

There are two hallmarks for the Alzheimer's disease that are currently used to identify the disease- the presence of the proteins Amyloid-β and Tau. Amyloid PET has been studied for a long time and many effective probes have been introduced, some approved by the FDA, including [¹⁸F]-florbetaben (Neuraceq), [¹⁸F]-florbetapir (Amyvid), [¹⁸F]-flutemetamol (Vizamyl). However, it was found that imaging of NFTs could give more accurate results as the accumulation of Tau could directly be correlated with neurodegeneration, which isn't the case for Amyloid-β. Amyloid PET is thereby a diagnostic tool, which can rather be used for confirming the absence of Alzheimer's Disease. Tau PET, which was found to be a potentially useful diagnostic tool was explored further as it can directly be associated with the extent of spread of the disease. This led to the discovery of many probes for Tau PET. The initial ones were non-selective for Tau over Aβ. Further exploration suggested two generations of Tau probes, both with higher selectivity for Tau over Aβ. A second generation was introduced to overcome the shortcomings of the first generation which are examined in this review. Much research on effective Tau PET probes has led to an FDA-approved Tau probe, ¹⁸F-flortaucipir. This systematic review discusses the characteristics and effectiveness of the first-generation probes, second-generation probes and other newer probes. It discusses the structural changes made in the probes over time that led to the enhancement of their properties as a Tau probe, that is, increased affinity and selectivity for Tau. It also discusses the shortcomings of probes developed so far and the ideal characteristics for Tau probes.

The prognosis for mixed-lineage leukemia (MLL), particularly in young children, remains a significant health concern due to the limited therapeutic options available. MLL refers to KMT2A chromosomal translocations that produce MLL fusion proteins. The protein menin, which is essential for the malignant potential of these MLL fusion proteins, offers novel targets for acute leukemia treatment. This study reports the identification of potential new inhibitors of MLL-mediated leukemia targeting menin through the screening of two distinct drug libraries and existing inhibitors. The 3D structure of the protein was retrieved from the Protein Data Bank (ID: 8IG0). The drug libraries, sourced from public repositories such as the 'Epigenetic Drug Library' and 'The FDA-anticancer Drug Library,' yielded top candidates like Tozaseritib and Panobinostat, which exhibited the highest binding energy scores in the Glide virtual screening module. Additionally, 31 known menin-MLL1 inhibitors were identified through PDB screening and subsequently docked with the menin protein. The top three inhibitors (M-525, M-808, and MI-89) were selected for further analysis. Five menin-ligand complexes were validated using molecular dynamics analysis and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations to verify the stability and binding mechanisms.These findings provide insights into the molecular mechanisms of these drugs and lay the groundwork for future clinical development aimed at improving outcomes for acute myeloid leukemia (AML) patients.

Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are defined by the accumulation of misfolded and aggregated proteins, which impair cellular function and result in progressive neuronal death. This chapter examines the critical function of proteostasis-cellular protein homeostasis-in sustaining neuronal health and its disruption as a key factor in disease progression. Proteostasis is upheld by a complex array of mechanisms, which encompass molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, and mitochondrial quality control. Impairment of these systems leads to protein misfolding and aggregation, resulting in toxic cellular environments that promote neurodegeneration. Novel therapeutic approaches focus on restoring proteostasis through the enhancement of cellular protein folding, degradation, and clearance mechanisms. This encompasses small molecule chaperones, gene therapy, RNA-based treatments, immunotherapy, autophagy inducers, and stem cell-based approaches, each addressing distinct components of the proteostasis network to mitigate or prevent disease progression. While these therapies show potential, challenges persist, such as possible side effects, selective targeting, and the efficacy of blood-brain barrier penetration. Personalized medicine and combination therapies customized to specific disease profiles are increasingly recognized for their potential to improve efficacy and safety. This chapter consolidates recent developments in therapies aimed at proteostasis, addresses the challenges encountered in clinical applications, and outlines potential future directions for transformative treatments. Ongoing research indicates that proteostasis modulation may significantly alter the course of neurodegenerative disease treatment, potentially enhancing patient outcomes and quality of life.

Cholesterol, produced by astrocytes, is vital for the formation and maintenance of synapse, highlighting the significance of lipid metabolism in neuronal health. Neural stem cells (NSCs) are versatile, self-renewing and capable of differentiating into neurons, astrocytes, and oligodendrocytes, playing a pivotal role in both embryonic development and adult neurogenesis. In the central nervous system (CNS), NSCs primarily reside in the subventricular zone (SVZ) and the sub-granular layer of the dentate gyrus, where they give rise to neural progenitors and subsequently to neurons and glial cells. Oligodendrocytes play a crucial role in the CNS function and myelin sheath formation, which is essential for rapid neuronal signal transmission. Astrocytes contribute to brain homeostasis by regulating lipid metabolism and providing metabolic support to neurons. Sphingolipids and phospholipids are integral to neural cell membrane structure and function, influencing processes such as neurogenesis, cell signaling, and synaptic plasticity. Furthermore, the ApoE4 allele impacts lipid metabolism, affecting the risk of neurodegenerative diseases. This paper explores the role of various cell types and lipids in the CNS, emphasizing the importance of lipid metabolism in maintaining neural function and the implications for neurodegenerative conditions.