Advances in protein chemistry and structural biology最新文献

{"title":"SUMO inhibits Tau aggregation in Alzheimer's disease.","authors":"Subashchandrabose Chinnathambi, Nagaraj Rangappa","doi":"10.1016/bs.apcsb.2025.02.001","DOIUrl":"10.1016/bs.apcsb.2025.02.001","url":null,"abstract":"<p><p>Tau is a microtubule-binding, hydrophilic protein and appears randomly coiled in circular dichroism spectra. Tau can have many post-translational modifications such as phosphorylation, acetylation, SUMOylation, glycation, ubiquitinylation, etc. The abnormal phosphorylation of Tau lowers its affinity to bind the microtubules, causing to neuronal instability. Hyperphosphorylated Tau can get detach from the microtubules and get aggregate in neuronal cell body to form a neurofibrillary tangle, which leads to weaken axonal transport and cause synaptic dysfunction. Tau itself is a SUMO-1 target protein and the modified lysine has been identified as the K340 located within 4R-Tau. The interaction between Tau and SUMO-1 was confirmed by an independent study, by showing that the SUMO-1 immunoreactivity is co-localized with phosphorylated Tau. In addition to this, Tau can also be ubiquitinated and degraded by the proteasome through both ubiquitin-dependent and ubiquitin-independent pathways. Our study shows that SUMOylation at lysine K340 stimulates Tau phosphorylation and inhibits ubiquitination-mediated Tau degradation, thus favouring its aggregation.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"147 ","pages":"355-374"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090900","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 antibodies to nanobodies: The next frontier in cancer theranostics for solid tumors.","authors":"Sanjana Mehrotra, Navdeep Kaur, Sukhpreet Kaur, Kawaljit Matharoo, Rajeev Kumar Pandey","doi":"10.1016/bs.apcsb.2024.10.014","DOIUrl":"10.1016/bs.apcsb.2024.10.014","url":null,"abstract":"<p><p>The field of cancer therapeutics has witnessed significant advancements over the past decades, particularly with the emergence of immunotherapy. This chapter traces the transformative journey from traditional antibody-based therapies to the innovative use of nanobodies in the treatment and diagnosis of solid tumors. Nanobodies are the smallest fragments of antibodies derived from camelid immunoglobulins and have redefined the possibilities in cancer theranostics due to their unique structural and functional properties. We provide an overview of the biochemical characteristics of nanobodies that make them particularly suitable for theranostic applications, such as their small size, high stability, enhanced infiltration into the complex tumor microenvironment (TME) and ability to bind with high affinity to epitopes that are inaccessible to conventional antibodies. Further, their ease of modification and functionalization has enabled the development of nanobody-based drug conjugates/toxins and radiolabeled compounds for precise imaging and targeted radiotherapy. We elucidate how nanobodies are being served as valuable tools for prognostic assessment, enabling clinicians to predict disease aggressiveness, monitor treatment response, and stratify patients for personalized therapeutic interventions.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"287-329"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466732","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":"Therapeutic insight into the role of nuclear protein HNF4α in liver carcinogenesis.","authors":"Soumik Das, Harini Ravi, V Devi Rajeswari, Ganesh Venkatraman, Magesh Ramasamy, Sivaraman Dhanasekaran, Gnanasambandan Ramanathan","doi":"10.1016/bs.apcsb.2024.05.001","DOIUrl":"10.1016/bs.apcsb.2024.05.001","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"143 ","pages":"1-37"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021814","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":"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":"Heat shock proteins regulates Tau protein aggregation in Alzheimer's disease.","authors":"Subashchandrabose Chinnathambi","doi":"10.1016/bs.apcsb.2024.08.003","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.08.003","url":null,"abstract":"<p><p>Alzheimer's disease is one of the neurodegenerative diseases characterized by loss of integrity and function of the cell, leading to progressive neuronal loss and ultimately dementia. Tau is one of the most soluble protein mainly involved in assembly and disassembly of microtubules (MT) which helps in the anterograde and retrograde transport of cargos. However in AD conditions Tau is subjected to various insults such as hyperphosphorylation, glycation, glycosylation, truncation, acetylation, oxidation etc., which leads to the loss-of-function. Thus modified Tau loses its affinity for MT and aggregates to form toxic oligomers followed by matured neurofibrillary tangles (NFTs) which attains cross-β structure. The cellular machinery such as chaperones, ubiquitin-proteasome system (UPS) and lysosomes tries to resolve these aggregates and helps in its clearance. During AD pathology the cellular machinery fails to clear aggregates and leads to neuronal death. In this aspect several strategies have been employed to prevent Tau aggregation that includes inhibitors for kinases, activators for phosphatases, small molecule activators of heat shock protein response and small molecules that can prevent Tau aggregation and increases its association with chaperones.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"146 ","pages":"161-178"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558788","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":"Tau protein aggregation: A therapeutic target for neurodegenerative diseases.","authors":"Aryan Duggal, Drishti Mahindru, Kirti Baghel, Sanjana Mehrotra, Vijay Kumar Prajapati","doi":"10.1016/bs.apcsb.2024.11.012","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.11.012","url":null,"abstract":"<p><p>Tau protein, a critical element for neuronal structure, becomes pathogenic in numerous neurodegenerative diseases, particularly Alzheimer's disease and other tauopathies. Under normal conditions, tau stabilizes microtubules and supports essential cellular transport systems. However, in disease states, tau undergoes abnormal modifications-most notably hyperphosphorylation-causing it to detach from microtubules and aggregate into neurofibrillary tangles. These aggregates disrupt neuronal function, leading to progressive cognitive and motor deficits. This chapter provides a comprehensive overview of tau's structural properties, normal cellular roles, and the cascade of pathological changes that transform it into a neurotoxic agent. We examine current therapeutic strategies targeting tau, including efforts to inhibit its phosphorylation, prevent aggregation, and enhance its clearance from cells. Approaches such as kinase inhibitors, immunotherapies, and gene-based therapies are discussed in the context of their potential to halt or slow disease progression. Additionally, recent advancements in diagnostic tools-such as tau-specific PET imaging and blood biomarkers-are highlighted as transformative for early detection of the disease .</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"146 ","pages":"77-136"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558792","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 aggregation propensity of Tau and amyloid-β in Alzheimer's disease.","authors":"Subashchandrabose Chinnathambi, Murugappan Kumarappan, Madhura Chandrashekar, Sneha Malik","doi":"10.1016/bs.apcsb.2024.10.004","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.10.004","url":null,"abstract":"<p><p>Alzheimer disease is a multifactorial disease and can be due to many factors which includes gene mutation, cellular stress, toxicity, neuroinflammation, biomolecules dyshomeostasis, organelle stress and dysfunction, age, gender, ethnicity and other medical conditions are correlate with AD. Alzheimer disease, a progressive neurodegenerative disease characterized by presence of amyloid plaques and neurofibrillary tangles. These protein aggregates cause neurodegeneration, leading to cognition decline, finally memory loss. During disease progression, cross talk between the factors one with each other making disease condition worsen. Cross-talk leads to several cellular changes mainly functional change in both neural and neuro-glial cells. The neuronal changes are mitochondrial dysfunction, endoplasmic reticulum stress and synaptic loss. The neuro-glial changes include demyelination, neuroinflammation and phagocytosis. This change releases few proteins in CSF and blood which can be used as biomarker.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"146 ","pages":"179-199"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558793","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":"Toward accurate in silico prediction of antigen binding affinities for antibody engineering.","authors":"Tuğçe Uluçay, Merve Arslan, Hatice Döşeme, Sibel Kalyoncu, Seyit Kale","doi":"10.1016/bs.apcsb.2024.11.006","DOIUrl":"10.1016/bs.apcsb.2024.11.006","url":null,"abstract":"<p><p>In clinical applications and life sciences research, antibodies represent an important diagnostic and therapeutic potential thanks to their high target affinity, specificity, and broad developability. While the antigen affinity, one of the primary success assessors of an antibody, can be measured at reasonably high precision and reliability, the scalability of the measurements can be cumbersome and limited. This is troubling because the affinity must be monitored throughout all steps of the developability approaches such as affinity maturation and humanization of an antibody. In this context, in silico approaches present a lucrative opportunity at a fraction of the cost and time typically invested in a comparable wet lab undertaking. In addition to their high-throughput potential, in silico approaches can provide an invaluable side product, i.e., identifying the molecular driving forces behind affinity. Here, we investigated the performance of six different high-throughput servers in two settings common in antibody engineering applications: (i) de novo prediction of the experimental antibody-antigen binding constants, and (ii) the free energy change in binding due to single point mutations. We find that the accuracy of these tools can be significantly low in the two regimes relevant to antibody development: (i) prediction of high-affinity binding, and (ii) prediction of favorable mutations. These issues are intricately related to the training sets used in the underlying models of these tools where high-affinity complexes and favorable point mutations are typically underrepresented. We showed that biophysical characteristics of single point mutations, especially changes in bulkiness and hydrophobicity, increase the prediction error. We argue that while the prediction of mutational impact can be predicted within one kcal per mol using re-parameterized versions of the present in silico tools, the de novo prediction of the affinity likely requires revisiting the underlying physical models behind these tools.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"147 ","pages":"21-35"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090884","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}