Advances in protein chemistry and structural biology最新文献

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.

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 .

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.

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.

Protein misfolding and aggregation play a pivotal role in the development of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's disease, and other related disorders. Proper protein folding is essential for cellular function, but due to the complexity of the folding process and external factors like genetic mutations, oxidative stress, and aging, misfolding is inevitable. These misfolded proteins often aggregate into toxic forms that disrupt cellular processes, leading to neuronal damage and cognitive decline. This chapter provides a comprehensive overview of molecular mechanisms behind protein misfolding, highlighting how these abnormal structures contribute to neurodegeneration. It also explores the role of the proteostasis network and its therapeutic potential in alleviating these processes. Focusing on multitarget therapeutic strategies, the chapter offers insights into promising approaches for addressing the root causes of neurodegenerative diseases while identifying key research gaps that could shape future treatment developments. By blending current knowledge with emerging therapeutic directions, this chapter provides a comprehensive and engaging perspective on combating the challenges of protein misfolding in neurodegeneration.

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.

Tau protein accumulation is one of the characteristic features of Alzheimer's disease (AD). Their accumulation is driven by the formation of intermediate toxic oligomers of Tau to the highly ordered neurofibrillary tangles. Cellular machineries engage different types of proteins such as, chaperone-co-chaperones complex, ubiquitin, kinases, proteases etc., to clear the aberrantly accumulated Tau protein which otherwise would cause neuronal death. In the milieu of proteotoxicity, it would be significant for the cell to follow a specific path for Tau clearance. Under this circumstance, cells express key proteins and other accessory proteins specific to the pathway. This is known to be dependent on the post-translational modifications and mutations associated with Tau. The processes involved maintenance of proteins homeostasis in cells collectively called proteostasis. The proteostasis involve the synthesis of proteins by ribosomes, protein folding mostly by chaperons and the degradation of improperly folded or unwanted proteins. Autophagy is the mechanism to eradicate unwanted, non-functional and toxic proteins from the cell. Proteostasis plays a pivotal role in maintaining the normal cellular environment in the expense of considerable amount of energy. AD is the prevalent type of dementia associated with aging, which is characterized by aggregation of Tau.

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.

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.