Advances in protein chemistry and structural biology最新文献

{"title":"Small molecule-mediated therapeutic approaches to target Tau and Alzheimer's disease.","authors":"Subashchandrabose Chinnathambi","doi":"10.1016/bs.apcsb.2024.11.010","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.11.010","url":null,"abstract":"<p><p>Neurodegeneration is marked by the altered proteostasis and protein degradation mechanism. This is caused due to the accumulation of aberrant proteins. Alzheimer's disease is one of the leading causes of neurodegeneration characterized by the aggregation of Tau and Amyloid-β proteins intracellularly and extracellularly, respectively. The intracellular aggregation of Tau triggers accumulation of oxidative stress, loss of ER and mitochondrial function, leading to the aggravation of aggregates formation. Thus, increasing the load of aberrant proteins on chaperones and degradative mechanism, such as autophagy and ubiquitin-proteasome system. Although several small molecules are known to target and prevent Tau aggregation, the detrimental effects in the cell due to aggregates accumulation shall not be overlooked. In such instance, small molecules that effectively target Tau aggregates and the cellular aberrations would be of great importance. Here we have discussed the efficacy of natural molecule, Limonoid, isolated from Azadirachta indica that prevents Tau aggregation and also activates the heat shock protein system. The activated heat shock protein system elevates the levels of Hsp70 that is known to interact with aberrantly folded Tau. Further, the role of Hsp70 in directing Tau clearance by macroautophagy or chaperone-mediated autophagy elucidates the effect of limonoids in overcoming AD pathology due to Tau aggregation.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"145 ","pages":"287-304"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring therapeutic strategies based on chaperon-mediated disaggregation.","authors":"Leandro Rocha Silva, Sheila Oliveira de Souza, Ana Catarina Rezende Leite, Edeildo Ferreira da Silva-Júnior","doi":"10.1016/bs.apcsb.2024.11.003","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.11.003","url":null,"abstract":"<p><p>In the quest to develop effective therapeutic strategies for diseases associated with protein misfolding and aggregation, molecular chaperones have emerged as pivotal players. This chapter explores the role of chaperones, such as Hsp40, Hsp70, and Hsp90, in mediating the disaggregation of misfolded proteins and facilitating proper folding under stress conditions. Despite their lack of sequence specificity, these proteins adeptly recognize exposed hydrophobic regions in partially folded states, thereby preventing aggregation and promoting functional conformations. The intricate network of chaperone interactions is crucial for maintaining cellular homeostasis and mitigating the pathological consequences of protein misfolding, particularly in conditions like Alzheimer's disease and various cancers. Innovative therapeutic approaches, including the use of pharmacological and chemical chaperones, aim to restore functionality to mutated or misfolded proteins, exemplified by interventions targeting the ΔF508 mutation in CFTR. While promising, the modulation of chaperone activity must be carefully calibrated to avoid disrupting cellular functions. This chapter highlights the potential of chaperone-mediated disaggregation as a therapeutic strategy, addressing both the current advancements and the challenges that lie ahead in harnessing these proteins for clinical benefit.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"145 ","pages":"219-254"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preface.","authors":"Dr Vijay Kumar Prajapati","doi":"10.1016/S1876-1623(25)00019-7","DOIUrl":"https://doi.org/10.1016/S1876-1623(25)00019-7","url":null,"abstract":"","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"xix"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of protein aggregates in bacteria.","authors":"Ewa Laskowska, Dorota Kuczyńska-Wiśnik, Karolina Stojowska-Swędrzyńska","doi":"10.1016/bs.apcsb.2024.09.012","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.09.012","url":null,"abstract":"<p><p>Protein misfolding and aggregation in bacteria, induced by a variety of intrinsic and environmental stresses, have often been associated with proteostasis disruption and toxic effects. However, a growing body of evidence suggests that these aggregates may also serve as functional membrane-less organelles (MLOs), playing a protective role in bacterial cells. The main mechanism responsible for the formation of MLOs is liquid-liquid phase separation (LLPS), a process that transforms a homogenous solution of macromolecules into dense condensates (liquid droplets) and a diluted phase. Over time, these liquid droplets can be transformed into solid aggregates. Bacterial MLOs, containing one dominant component or hundreds of cytoplasmic proteins, have been shown to be involved in various processes, including replication, transcription, cell division, and stress tolerance. The protective function of bacterial MLOs involves sequestration and protection of proteins and RNA from irreversible inactivation or degradation, upregulation of molecular chaperones, and induction of a dormant state. This protective role is particularly significant in the case of pathogenic bacteria exposed to antibiotic therapy. In a dormant state triggered by protein aggregation, pathogens can survive antibiotic therapy as persisters and, after resuming growth, can cause recurrent infections. Recent research has explored the potential use of bacterial MLOs as nanoreactors that catalyze biochemical reactions or serve as protein reservoirs and biosensors, highlighting their potential in biotechnology.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"145 ","pages":"73-112"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear Tau accumulation in Alzheimer's disease.","authors":"Subashchandrabose Chinnathambi, Gowshika Velmurugan, Swathi Suresh, Anusree Adithyan, Madhura Chandrashekar","doi":"10.1016/bs.apcsb.2024.06.003","DOIUrl":"10.1016/bs.apcsb.2024.06.003","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"143 ","pages":"323-337"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring immunotherapy to control human infectious diseases.","authors":"Praveen Rai, Sanjana Mehrotra, Vijay Kumar Prajapati","doi":"10.1016/bs.apcsb.2024.10.010","DOIUrl":"10.1016/bs.apcsb.2024.10.010","url":null,"abstract":"<p><p>Infectious diseases continue to pose significant challenges to global health, especially with the rise of antibiotic resistance and emerging pathogens. Traditional treatments, while effective, are often limited in the face of rapidly evolving pathogens. Immunotherapy, which harnesses and enhances the body's immune response, offers a promising alternative to conventional approaches for the treatment of infectious diseases. By employing use of monoclonal antibodies, vaccines, cytokine therapies, and immune checkpoint inhibitors, immunotherapy has demonstrated considerable potential in overcoming treatment resistance and improving patient outcomes. Key innovations, including the development of mRNA vaccines, use of immune modulators, adoptive cell transfer, and chimeric antigen receptor (CAR)-T cell therapy are paving the way for more targeted pathogen clearance. Further, combining immunotherapy with conventional antibiotic treatment has demonstrated effectiveness against drug-resistant strains, but this chapter explores the evolving field of immunotherapy for the treatment of bacterial, viral, fungal, and parasitic infections. The chapter also explores the recent breakthroughs and ongoing clinical trials in infectious disease immunotherapy.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"389-429"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy in the management of inflammatory bone loss in osteoporosis.","authors":"Leena Sapra, Rupesh K Srivastava","doi":"10.1016/bs.apcsb.2024.10.013","DOIUrl":"10.1016/bs.apcsb.2024.10.013","url":null,"abstract":"<p><p>Osteoporosis, a progressive skeletal disorder characterized by decreased bone mass and increased fracture risk, has traditionally been treated with pharmacological agents targeting bone remodeling. However, emerging research highlights the critical role of immune system in regulating bone metabolism, introducing the concept of Osteoimmunology. Chronic low-grade inflammation is now recognized as a significant contributor to osteoporosis, particularly in postmenopausal women and the elderly. Immune cells, such as T cells and B cells, and their secreted cytokines directly influence bone resorption and formation, tipping the balance toward net bone loss in inflammatory environments. Immunotherapy, a treatment modality traditionally associated with cancer and autoimmune diseases, is now gaining attention in the management of osteoporosis. By targeting immune dysregulation and reducing inflammatory bone loss, immunotherapies offer a novel approach to treating osteoporosis that goes beyond merely inhibiting bone resorption or promoting bone formation. This therapeutic strategy includes monoclonal antibodies targeting inflammatory cytokines, cell-based therapies to enhance the function of regulatory T and B cells, and interventions aimed at modulating immune pathways linked to bone health. This chapter reviews the emerging role of immunotherapy in addressing inflammatory bone loss in osteoporosis. Present chapter also explores the underlying immune mechanisms contributing to bone degradation, current immunotherapeutic strategies under investigation, and the potential of these approaches to revolutionize the management of osteoporosis.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"461-491"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of lamins in cellular physiology and cancer.","authors":"Ravi Chauhan, Ashna Gupta, Gunjan Dagar, Shalini Sharma, Hana Q Sadida, Sheema Hashem, Ann M Verghese, Mukesh Tanwar, Muzafar A Macha, Shahab Uddin, Ammira S Al-Shabeeb Akil, Tej K Pandita, Ajaz A Bhat, Mayank Singh","doi":"10.1016/bs.apcsb.2024.06.002","DOIUrl":"10.1016/bs.apcsb.2024.06.002","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"143 ","pages":"119-153"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From infection to remedy: Harnessing oncolytic viruses in cancer treatment.","authors":"Sramona Kar, Sanjana Mehrotra, Vijay Kumar Prajapati","doi":"10.1016/bs.apcsb.2024.10.012","DOIUrl":"10.1016/bs.apcsb.2024.10.012","url":null,"abstract":"<p><p>Oncolytic virus (OV) mediated immunotherapy is one of the recent techniques used to treat higher grade cancers where conventional therapies like chemotherapy, radiation fail. OVs as a therapeutic tool show high efficacy and fewer side effects than conventional methods as supported by multiple preclinical and clinical studies since they are engineered to target tumours. In this chapter, we discuss the modifications in viruses to make them oncolytic, types of strains commonly administered, mechanisms employed by viruses to specifically target and eradicate malignancy and progress achieved as reported in case studies (preclinical and clinical trials). OVs also face some unique challenges with respect to the malignancy being treated and the varied pathogen exposure of the patients, which is also highlighted here. Since pathogen exposure varies according to population dynamics worldwide, chances of generating a non-specific recall response to an OV cannot be negated. Lastly, the future perspectives and ongoing practises of combination therapies are discussed as they provide a leading edge over monotherapies in terms of tumour clearance, blocking metastasis and enhancing patient survival. Efforts undertaken to overcome current challenges are also highlighted.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"213-257"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accurate coarse grained models for protein association and recognition.","authors":"Agustí Emperador, Elvira Guàrdia","doi":"10.1016/bs.apcsb.2024.11.011","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.11.011","url":null,"abstract":"<p><p>Protein-protein interactions are fundamental to the cell function, but some of them are slow processes happening in time scales in the microsecond to millisecond range, therefore inaccessible for standard atomistic molecular dynamics (MD) simulations. A way to reduce the computational cost demanded by the simulation of long timescale phenomena is to use coarse-grained (CG) models to reduce the number of particles included in the simulation. In this Review we provide an overview of CG models for the study of protein dynamics and interactions. The majority of protein CG models have been designed to describe accurately the structure of folded, stable proteins, but recently new CG models and force fields have been designed to study disordered proteins. The difficulty of finding a force field fully transferable between stable and disordered proteins hinders the computational study of the intracellular environment in its most complex case, where protein-protein interactions occur in multiprotein systems constituted by both stable and disordered proteins. In this Review we overview several existing CG protein models, focusing on its applicability to the study of multiprotein systems including both stable and disordered proteins. We also discuss the utility of implicit solvent models, which accelerate the conformational sampling of protein solutions, to explore a broader configurational space of the system in shorter simulation times, and analyze the inaccuracies inherent to this approximation.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"145 ","pages":"1-21"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}