Advances in protein chemistry and structural biology最新文献

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.

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.

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.

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.

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.

Hepatocyte nuclear factor 4-alpha (HNF4α), a well-preserved member of the nuclear receptor superfamily of transcription factors, is found in the liver. It is recognized as a central controller of gene expression specific to the liver and plays a key role in preserving the liver's homeostasis. Irregular expression of HNF4α is increasingly recognized as a crucial factor in the proliferation, cell death, invasiveness, loss of specialized functions, and metastasis of cancer cells. An increasing number of studies are pointing to abnormal HNF4α expression as a key component of cancer cell invasion, apoptosis, proliferation, dedifferentiation, and metastasis. Understanding HNF4α's intricate involvement in liver carcinogenesis provides a promising avenue for therapeutic intervention. This chapter attempts to shed light on the diverse aspects of HNF4's role in liver carcinogenesis and demonstrate how this knowledge can be harnessed for approaches to prevent and treat liver cancer. This comprehensive chapter will offer an elaborate perspective on HNF4's function in liver cancer, delineating its molecular mechanisms that aid in the emergence of liver cancer. Furthermore, it will highlight the potential to help create more effective and precisely targeted therapeutic strategies, rekindling fresh optimism in the fight against this formidable condition.

Tau is a well-known microtubule-associated protein and is located in the cytoplasm of neurons, which play a crucial role in Alzheimer's diseases. Due to its preferred binding to DNA sequences found in the nucleolus and pericentromeric heterochromatin, Tau has been found within the cell nucleus, where it may be a nucleic acid-associated protein. Tau has the ability to directly interact with nuclear pore complex nucleoporins, influencing both their structural and functional integrity. The interaction between Tau and NUPs highlights a potential mechanism underlying NPC dysfunction in AD pathogenesis. Pathological Tau hinders the import and export of nucleus through RAN mediated cascades. Nuclear Tau aggregates colocalize with membrane less organelles called nuclear speckles, which are involved in pre-mRNA splicing, and modify their dynamics, composition, and structure. Additionally, SRRM2 and other nuclear speckle proteins including MSUT2 and PABPN1 mislocalize to cytosolic Tau aggregates, and causes propagation of Tau aggregates. Research highlights, Extracellular Tau Oligomers induce significant nuclear invagination. They act as a key player in the transformation of healthy neurons into sick neurons in AD. The mechanism behind this phenomenon depends on intracellular Tau and is linked to changes in chromatin structure, nucleocytoplasmic transport, and gene transcription. This review highlights the vital roles of nuclear Tau protein in the context of nuclear pore complex functioning and, modulation of nuclear speckles in Alzheimer's diseases. Addressing these pathways is essential for formulating focused therapeutics intended to alleviate Tau-induced neurodegeneration.

Lamins, which are crucial type V intermediate filament proteins found in the nuclear lamina, are essential for maintaining the stability and function of the nucleus in higher vertebrates. They are classified into A- and B-types, and their distinct expression patterns contribute to cellular survival, development, and functionality. Lamins emerged during the transition from open to closed mitosis, with their complexity increasing alongside organism evolution. Derived from the LMNA, LMNB1, and LMNB2 genes, lamins undergo alternative splicing to produce seven variants, influencing cellular processes such as stiffness, chromatin condensation, and cell cycle regulation. The lamin network interacts with the cytoskeleton via Linkers of the nucleoskeleton to the cytoskeleton (LINC) complexes, playing a critical role in cellular stability and mechanotransduction. Lamins also regulate active transport into and out of the nucleus, affecting nuclear integrity, positioning, DNA maintenance, and gene expression. Genetic mutations in lamin genes lead to laminopathies, highlighting their functional significance and organizational roles. Changes in lamin subtype composition within the nuclear lamina have significant implications for cancer development, impacting cellular stiffness, mobility, and the Epithelial-to-Mesenchymal Transition (EMT). Lamin A/C, in particular, plays multifaceted roles in cancer biology, influencing progression, metastasis, and therapy response through interactions with various proteins and pathways. Dysregulated lamin expression is commonly observed in cancers, suggesting their potential as diagnostic and prognostic markers. This chapter underscores the pivotal roles of lamins in nuclear architecture and cancer biology, emphasizing their impact on cellular functions and disease pathology. Understanding lamin behavior and regulation mechanisms holds promise for developing novel diagnostic tools and targeted therapies in cancer treatment.

Nuclear protein transcription factors (TFs) regulate all biological processes in plants and are necessary for gene regulation. The transcription of genes during plant growth and development and their response to environmental cues are regulated by TF binding to specific promoter regions in the genomic DNA. Polyploid plants with several sets of chromosomes frequently display intricate genomic biases concerning TF expression. One or more subgenomes may dominate in terms of gene expression, leading to subgenome biases or dominance. These biases can influence various aspects of the crop's biology, including its growth, development, and adaptation. Advances in genomics have speed up the improvement of many important agricultural diploid crops, yet comparable endeavours in polyploid crops have been more challenging. This challenge primarily stems from the large size and intricate nature of the complex genome in polyploid crops, along with the need for comprehensive genome assembly data for such crop varieties as bread wheat, cotton and sugarcane. Several studies have evaluated the biased/asymmetric gene expression patterns, including TFs, within the polyploid crop genomes. In many polyploid crops, not all homologues of TF genes contribute equally to the phenotype. Here, we have examined polyploid crop plants for homeolog gene expression, emphasizing TFs. It is observed that the polyploids retain many gene alleles as functional homeologs that define important features involved in stress response, sugar metabolism, and fibre formation. The possible molecular mechanism describing the structural and epigenetic basis of differential subgenomic TF expression in polyploids is discussed.