Advances in protein chemistry and structural biology最新文献

{"title":"Nuclear podosomes regulates cellular migration in Tau and Alzheimer's disease.","authors":"Tazeen Qureshi, Madhura Chandrashekar, Vaishnavi Ananthanarayana, Murugappan Kumarappan, Nagaraj Rangappa, Gowshika Velmurugan, Subashchandrabose Chinnathambi","doi":"10.1016/bs.apcsb.2024.09.009","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.09.009","url":null,"abstract":"<p><p>The neuronal cytoskeleton has remained a less explored area of research in establishing neuroprotection. HDAC6 has been studied with respect to many neurodegenerative diseases, especially AD. It exhibits the ability to interact with various cytoskeletal proteins and to promote migration in cells. Podosomes are actin microstructures that help cells to migrate in the extracellular environment. The aim of this review is to bring into focus the significance of studies on the involvement of podosomes in Alzheimer's disease. We have suggested that Histone Deacetylase 6 plays a vital role in AD, through its interactions with the various signalling processes in the cell, most importantly the cytoskeletal remodelling machinery within the podosomes.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"143 ","pages":"411-426"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021796","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 transport protein suppresses Tau neurodegeneration.","authors":"Subashchandrabose Chinnathambi, Anusree Adithyan, Swathi Suresh, Gowshika Velmurugan, Madhura Chandrashekar, Surajita Sahu, Monalisa Mishra","doi":"10.1016/bs.apcsb.2024.07.001","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.07.001","url":null,"abstract":"<p><p>The nuclear pore complex, a large multimeric structure consists of numerous protein components, serves as a crucial gatekeeper for the transport of macromolecules across the nuclear envelope in eukaryotic cells. Dysfunction of the NPC has been implicated in various neurodegenerative diseases, including Alzheimer's disease. In AD, Tau aggregates interact with NPC proteins, known as nucleoporins, leading to disruptions in nuclear transport. Hyperphosphorylated Tau, a hallmark of AD pathology, interacts with central channel NUPs such as Nup62 and Nup98, causing cytoplasmic mis-localization of these proteins and impairing nuclear transport. Furthermore, Tau-NUP interactions promote Tau aggregation and the formation of neurofibrillary tangles, exacerbating neurodegeneration. Oligomeric Tau adheres to the lamin B receptor as well as nuclear lamin, preventing nucleocytoplasmic transport and resulting in heterochromatin unwinding, DNA damage, and neuronal death. The decrease in lamin B and increasing levels of lamin A along with C in AD-affected brain areas highlight the disease's intricacy. Furthermore, Tau internalization in the nucleus and interaction with nuclear pore complexes worsen NPC dysfunction, which contributes to neurotoxicity. Tau-DNA interactions suggest a chaperone-like role for Tau in DNA organization and repair, highlighting its involvement in maintaining genomic integrity. This review explores the intricate relationships between Tau, NPC components, and nuclear lamin in the context of AD, providing insights into the mechanisms underlying Tau-induced neurodegeneration and potential therapeutic targets.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"143 ","pages":"363-385"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021801","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":"Revolutionizing pancreatic cancer treatment with CAR-T therapy.","authors":"Kirti Baghel, Sanjana Mehrotra, Vijay Kumar Prajapati","doi":"10.1016/bs.apcsb.2024.10.008","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.10.008","url":null,"abstract":"<p><p>Pancreatic cancer remains one of the most lethal malignancies, with a five-year survival rate among the lowest of all cancers. This poor prognosis is largely due to the aggressive nature of the disease and its resistance to conventional treatments such as surgery, chemotherapy, and radiation therapy. Chimeric antigen receptor (CAR) T-cell therapy, a novel immunotherapeutic approach leverages the patient's own immune system to specifically target and eliminate cancer cells by genetically engineering T cells to express CARs that recognize tumor-specific antigens. While CAR-T therapy has demonstrated remarkable success in treating hematologic malignancies, its application to solid tumors like pancreatic cancer presents significant challenges. Recent advancements in CAR-T cell design, like the addition of co-stimulatory domains and dual-targeting CARs, have enhanced their efficacy against solid tumors. Additionally, strategies to modify the tumor microenvironment (TME), such as combining CAR-T therapy with immune checkpoint inhibitors and cytokine modulation, are being investigated to boost CAR-T cell activity against pancreatic cancer. Early-phase clinical trials targeting antigens such as carcinoembryonic antigen (CEA) and mesothelin (MSLN) in pancreatic cancer have yielded encouraging results, though obstacles like antigen escape and limited T-cell persistence remain significant challenges. This chapter outlines the current state of CAR-T therapy for pancreatic cancer, focusing on the emerging approaches to address these obstacles and underscore the potential of CAR-T therapy to transform the future of pancreatic cancer treatment.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"331-353"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466722","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 to CD5, a T-cell antigen having roles from development to peripheral function: Future prospective and challenges.","authors":"Ranjeet Bahadur Choubey, Sweta, Vibha, Avika Sharma, Ambak Kumar Rai","doi":"10.1016/bs.apcsb.2024.10.007","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.10.007","url":null,"abstract":"<p><p>CD5 is a pan T-cell marker expressed by all T-cells and a subset of B-cells, i.e., B1a cells. The significance of CD5 is evident from its functions, starting from T-cell development, antigen priming, activation, and effector response to the maintenance of tolerance. Varying CD5 expression and signaling in response to TCR-pMHC complex avidity is associated with thymic selection, competency, and effector response. Altered CD5 expression is associated with immunological and diseased conditions such as CD5^-/low infiltrating T-cells in solid tumors, CD5^hi T-cells in anergy conditions, CD5^-/low phenotype of leukemic T-cells, high CD5 expression by regulatory T-cells, CD5^lowphenotype of autoreactive T-cells, etc. A low CD5 expression triggers activation-induced cell death upon antigenic stimulation. There are three forms of CD5: membrane CD5 (mCD5), intracellular CD5 (cCD5) and soluble CD5 (sCD5). mCD5 and cCD5 are generated from conventional and non-conventional mRNA variants, i.e., E1A and E1B, respectively. E1B variant encoding cCD5 is derived from a human endogenous retrovirus segment inserted 8.2 kb upstream to conventional E1A exon. Various conditions, such as leukemia, exposure to hydrocarbon, hypoxia, etc., can trigger E1B transcription and, thus, cCD5 expression. Blocking mCD5 with mAb can restore immune response, effectively targeting cancer. Understanding cCD5, linked to leukemogenesis, can offer new avenues of immunotherapy.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"431-460"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466748","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":"Leveraging nuclear receptor mediated transcriptional signaling for drug discovery: Historical insights and current advances.","authors":"Riya Ben Patel, Surbhi Kumari Barnwal, Arabi Mohammed Saleh M A, Dileep Francis","doi":"10.1016/bs.apcsb.2024.10.001","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.10.001","url":null,"abstract":"<p><p>Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression in response to physiological signals, such as hormones and other chemical messengers. These receptors either activate or repress the transcription of target genes, which in turn promotes or suppresses physiological processes governing growth, differentiation, and homeostasis. NRs bind to specific DNA sequences and, in response to ligand binding, either promote or hinder the assembly of the transcriptional machinery, thereby influencing gene expression at the transcriptional level. These receptors are involved in a wide range of pathological conditions, including cancer, metabolic disorders, chronic inflammatory diseases, and immune system-related disorders. Modulation of NR function through targeted drugs has shown therapeutic benefits in treating such conditions. NR-targeted drugs, which either completely or selectively activate or block receptor function, represent a significant class of clinically valuable therapeutics. However, the pathways of NR-mediated gene expression and the resulting physiological effects are complex, involving crosstalk between various biomolecular components. As a result, NR-targeted drug discovery is challenging. With improved understanding of how NRs regulate physiological functions and deeper insights into their molecular structure, the process of NR-targeted drug discovery has evolved. While many traditional NR-targeting drugs are associated with side effects of varying severity, new drug candidates are being designed to minimize these adverse effects. Given that NR activity varies according to the tissue in which they are expressed and the specific isoform that is activated or repressed, achieving selectivity in targeting specific tissues and isoform classes may help reduce systemic side effects. In a recent breakthrough, the isoform-selective, hepato-targeted thyroid hormone-β agonist, Resmetirom (marketed as Rezdiffra), was approved for the treatment of non-alcoholic steatohepatitis. This chapter explores the structural and mechanistic principles guiding NR-targeted drug discovery and provides insights into recent developments in this field.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"143 ","pages":"191-269"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021789","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":"Monoclonal antibodies - A repertoire of therapeutics.","authors":"Suman Tapryal","doi":"10.1016/bs.apcsb.2024.11.001","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.11.001","url":null,"abstract":"<p><p>Antibodies are a class of biomolecules armed with extraordinary diversity, unmatched in the biological world by any other class of molecules. This characteristic feature equips antibodies to recognize, bind, and eliminate an infinite number of pathogens/antigens facilitated by their effector functions. The repertoire of natural binding specificities of antibodies (Abs) is greater than the calculated estimate of ∼10¹² in humans, as a naive, single antigen-binding site may bind more than one antigen employing the plasticity in antigen-antibody interactions, potentiating Abs to fight infinite pathogenic insults and restrict the development of cancers. Additionally, advanced technological interventions, by allowing manipulation of the germline and acquired specificities of human/animal immunoglobulins (Ig) have contributed immensely to broaden their existing repertoire and scope of clinical applications. The available natural repertoire of Ig and Ig-like molecules in other animals, e.g., mice, horses, cows, pigs, rabbits, camels, llamas, etc., further diversified the source of unique antigen-binding specificities. The recombinant DNA technology, in association with hybridoma , transgenic, and phage display technologies, has helped create a parallel repertoire of unique antibody molecules [animal Abs, camelid heavy chain Abs (hcAbs), chimeric Abs, chimeric hcAbs, humanized Abs, humanized nanobody (Nb)-hcAbs, human Abs, etc.], monoclonal Ab (mAb) derived fragments [antigen-binding-fragment (Fab), single-chain-variable-fragment (scFv), variable-fragement (Fv), single-variable-domain of hcAbs (V_HH), bispecific scFv, diabodies, triabodies, intrabodies, bispecific Fabs, tri-specific Fabs, etc.), and immunoconjugates generated by fusing/conjugating mAb fragments with enzyme, toxin, prodrug etc., molecules. The current chapter provides a detailed description of the natural and engineered antibody repertoires and discusses various strategies using which these molecules are being inducted as novel immunotherapeutics for treating a significant number of human diseases.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"151-212"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466650","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 with antibody-drug conjugates in solid tumor oncology.","authors":"Takhellambam Malemnganba, Anurag Kumar Pandey, Amit Mishra, Sanjana Mehrotra, Vijay Kumar Prajapati","doi":"10.1016/bs.apcsb.2024.10.016","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.10.016","url":null,"abstract":"<p><p>Immunotherapy has emerged as a hallmark of hope in the formidable battle against solid tumors such as breast cancer, colorectal cancer, etc., with antibody-drug conjugates (ADCs) starting a new era of precision medicine. This chapter delves into the dynamic landscape of immunotherapeutic strategies, focusing on the transformative potential of ADCs. ADCs represent a combination of chemotherapy and immunotherapy, more innovative chemotherapy. We emphasize the intricate interplay between tumor biology and therapeutic intervention, uncovering the mechanisms underlying ADC efficacy and the hurdles they must overcome. Each facet of ADC development is carefully examined, from the delicate balance between payload potency and safety to the quest for enhanced tumor penetration. We also elucidate the synergistic potential of combining ADCs with existing modalities, including chemotherapy and radiation therapy, to amplify therapeutic outcomes while mitigating adverse effects. As we navigate the complexities of solid tumor oncology, a profound understanding of the immunotherapeutic potential of ADCs is gained, offering hope for a cure for patients and clinicians alike. Henceforth, we delve into this transformative journey as we advance in solid tumor treatment regimens using immunotherapy with ADCs, poised at the forefront of oncological innovation.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"259-286"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466729","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":"cirCodAn: A GHMM-based tool for accurate prediction of coding regions in circRNA.","authors":"Denilson Fagundes Barbosa, Liliane Santana Oliveira, Pedro Gabriel Nachtigall, Rodolpho Valentini Junior, Nayane de Souza, Alexandre Rossi Paschoal, André Yoshiaki Kashiwabara","doi":"10.1016/bs.apcsb.2023.11.012","DOIUrl":"10.1016/bs.apcsb.2023.11.012","url":null,"abstract":"<p><p>Studies focusing on characterizing circRNAs with the potential to translate into peptides are quickly advancing. It is helping to elucidate the roles played by circRNAs in several biological processes, especially in the emergence and development of diseases. While various tools are accessible for predicting coding regions within linear sequences, none have demonstrated accurate open reading frame detection in circular sequences, such as circRNAs. Here, we present cirCodAn, a novel tool designed to predict coding regions in circRNAs. We evaluated the performance of cirCodAn using datasets of circRNAs with strong translation evidence and showed that cirCodAn outperformed the other tools available to perform a similar task. Our findings demonstrate the applicability of cirCodAn to identify coding regions in circRNAs, which reveals the potential of use of cirCodAn in future research focusing on elucidating the biological roles of circRNAs and their encoded proteins. cirCodAn is freely available at https://github.com/denilsonfbar/cirCodAn.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"139 ","pages":"289-334"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048541","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":"Motor proteins, spermatogenesis and testis function.","authors":"Lingling Wang, Tiao Bu, Xiaolong Wu, Linxi Li, Fei Sun, C Yan Cheng","doi":"10.1016/bs.apcsb.2024.03.003","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.03.003","url":null,"abstract":"<p><p>The role of motor proteins in supporting intracellular transports of vesicles and organelles in mammalian cells has been known for decades. On the other hand, the function of motor proteins that support spermatogenesis is also well established since the deletion of motor protein genes leads to subfertility and/or infertility. Furthermore, mutations and genetic variations of motor protein genes affect fertility in men, but also a wide range of developmental defects in humans including multiple organs besides the testis. In this review, we seek to provide a summary of microtubule and actin-dependent motor proteins based on earlier and recent findings in the field. Since these two cytoskeletons are polarized structures, different motor proteins are being used to transport cargoes to different ends of these cytoskeletons. However, their involvement in germ cell transport across the blood-testis barrier (BTB) and the epithelium of the seminiferous tubules remains relatively unknown. It is based on recent findings in the field, we have provided a hypothetical model by which motor proteins are being used to support germ cell transport across the BTB and the seminiferous epithelium during the epithelial cycle of spermatogenesis. In our discussion, we have highlighted the areas of research that deserve attention to bridge the gap of research in relating the function of motor proteins to spermatogenesis.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"141 ","pages":"381-445"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496831","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":"The crosstalk between extracellular matrix proteins and Tau.","authors":"Subashchandrabose Chinnathambi, Smita Eknath Desale","doi":"10.1016/bs.apcsb.2024.04.002","DOIUrl":"10.1016/bs.apcsb.2024.04.002","url":null,"abstract":"<p><p>Alzheimer's disease is progressive neurodegenerative disease characterize by the presence of extracellular accumulation of amyloid-β plaques and intracellular deposits of neurofibrillary tangles of Tau. Apart from axonal depositions pathological aggregated Tau protein is known to secrete into extracellular spaces and propagate through seeding mechanism. Microglia, the immune cells of the brain display modest ability to internalize the extracellular Tau and degrade it through endolysosomal pathway. However, the excessive burden of pathoproteins weakens the phagocytic ability of microglia. Extracellular supplementation of omega-3 fatty acids (n-3) may regulate the phagocytosis of microglia as they mediate the anti-inflammatory polarization of microglia through membrane lipid compositions changes. The internalization of extracellular Tau in the microglia is regulated by cortical membrane-associated actin remodeling driven by interplay of actin-binding proteins. On the other hand, Tau display capability bind and interact with various actin-binding protein owing to the presence of proline-rich domain in the structure and regulate their activation. In this study, we hypothesize that internalization of Tau in the presence of omega-3 fatty acids would propagate the Tau-mediated activation of actin-binding proteins as well as extracellular matrix and in turn modulate cortical actin remodeling for phagocytosis.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"141 ","pages":"447-466"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496833","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}