Biochemical Society transactions最新文献

Microtubule inner proteins (MIPs) are integral components within the microtubule lumen of various organisms, contributing to microtubule structural integrity and functionality. Apicomplexan parasites, including Plasmodium spp. and Toxoplasma gondii, exhibit a range of specialized tubulin structures, such as axonemal microtubules, subpellicular microtubules (SPMTs), and conoid fibers, playing critical roles in cellular morphology and motility. Yet, in contrast with model organisms, only a few MIPs have been characterized in apicomplexans so far. Recent advances in cryo-electron tomography and structural proteomics have facilitated the study of MIPs, shedding light on unique adaptations that distinguish apicomplexan microtubules from those in model eukaryotes. Key findings include the identification of an interrupted luminal helix in SPMTs, which is critical for stabilizing microtubules under stress. The relatively small repertoire of axonemal MIPs contrasts markedly with the numerous MIPs observed in other systems, possibly reflecting adaptations for rapid microtubule assembly without intraflagellar transport. Furthermore, emerging evidence points to multiple MIPs within the conoid and SPMTs, suggesting further roles for MIPs in these parasites. This review highlights the currently known contributions of MIPs to the survival and proliferation of these parasites, while emphasizing the need for continued research to fully characterize their diverse roles and molecular mechanisms.

Asymmetric cell division (ACD) has been extensively studied in various stem cell systems as a fundamental mechanism that ensures the balance between stem cell self-renewal and differentiation. ACD allows one daughter cell to retain stem cell identity while the other commits to differentiation, thereby maintaining tissue homeostasis over time. Stem cells also undergo symmetric cell division, in which both daughter cells adopt either stem or differentiated fates. What are the outcomes of each cell division mode, and how strictly are these modes executed across different stem cell systems? There have been technical challenges of visualizing stem cell division in vivo due to the structural complexity of tissues and the rarity and ambiguous identity of genuine stem cells. Despite these difficulties, recent technical advancements have revealed how these cells operate within their native environments. This review summarizes key studies that elucidate distinct division modes and their functional outcomes across various stem cell systems.

The Ton and Tol-Pal systems are molecular machines that are essential for survival of Gram-negative bacteria.Both use the energy derived from the proton gradient at the inner membrane to generate force on protein components at the outer membrane. Ton and Tol share extensive homology, but they fulfill different functions: Ton is involved in the active transport of essential nutrients from the extracellular media into the cell, while Tol maintains the outer membrane integrity and participates in the cell division process. Despite decades of biochemical and biophysical studies, the molecular mechanism coupling the proton gradient at the inner membrane with the propagation of force and movement to the outer membrane is not understood. In this review, we discuss the recent high-resolution structures obtained for both systems, and how these structures fit with existing mechanistic models.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that has garnered extensive interest since its discovery as an oncogene product in the 1980s. We now understand that the binding of soluble growth factors to EGFR activates it by facilitating receptor-mediated EGFR dimerization. However, how the extracellular ligand-binding and intracellular tyrosine kinase domains communicate across the bilayer remains unclear. This lack of understanding likely originates from a 'divide and conquer' approach that has provided a detailed understanding of the respective domains in isolation but only limited knowledge of how they are co-ordinated during signaling. Attempts to study full-length EGFR in detergents or membrane environments that lack possible key lipid cofactors leave a critical component of intact receptor signaling understudied. Indeed, multiple classes of lipids, such as gangliosides and PtdIns(4,5)P2, have long been known to influence EGFR signaling in cells, and a lack of their inclusion in in vitro studies has hindered mechanistic understanding of the intact receptor. This review highlights recent studies of how lipids regulate EGFR activity, with special attention paid to potentially actionable co-dependent lipid metabolism in glioblastoma multiforme and promising new methods for studying membrane protein-bilayer interactions.

Enzymes are dynamic entities, and their conformational dynamics are intimately linked to their function and evolvability. In this context, protein tyrosine phosphatases (PTPs) are an excellent model system to probe the role of conformational dynamics in enzyme function and evolution. They are a genetically diverse family of enzymes, with a highly conserved catalytic domain, identical catalytic mechanisms, and turnover numbers that vary by orders of magnitude, with their activity being determined by the mobility of a catalytic loop that closes over the active site and places a key catalytic residue in place for efficient catalysis. From a biological perspective, PTPs are important regulators of a host of cellular processes, including cellular signaling, which has made them in particular important anticancer drug targets, among other diseases of interest. The high structural conservation of their active sites renders them therapeutically elusive, but there exist allosteric inhibitors that exploit the allosteric regulation of these enzymes to impede the motion of their catalytic WPD-loops, thus inactivating them. Conformational dynamics and allostery are problems that are ideal for computational investigation, and indeed, advances in computational methodologies have resulted in a range of exciting studies illuminating the molecular details of structure-function-dynamics-allostery links in these enzymes. This review provides both a brief history of computational work in this space, as well as discussing in detail recent advances, illustrating how molecular simulations have been successfully exploited to enhance our fundamental understanding of these biomedically important enzymes, and of the function and regulation of 'loopy' enzymes more broadly.

Aquaporins (AQPs) are crucial membrane proteins that primarily facilitate water transport across cell membranes. In the kidneys, AQP1, AQP7, AQP8, and AQP11 are expressed in the proximal tubules. AQP1 is also localized to the thin descending limb of the loop of Henle. AQP2, AQP3, AQP4, AQP5, and AQP6 are expressed in the collecting ducts. Specific AQPs, such as aquaglyceroporins and peroxiporins, also transport solutes like glycerol and hydrogen peroxide, indicating their broader physiological roles beyond water permeability. Renal AQPs play a fundamental role in urine concentration and maintaining water balance. However, some studies using AQP knockout mouse models have reported structural abnormalities in the renal tubules, along with defective water handling. These findings highlight the involvement of AQPs in regulating cell proliferation, migration, and apoptosis, which are essential processes for maintaining tubular integrity. Furthermore, aquaglyceroporins and peroxiporins are implicated in modulating cellular redox balance and contributing to oxidative stress responses that are also associated with tubular damage. This review explores how AQPs are regulated under physiological conditions and how they become dysregulated in kidney diseases such as acute kidney injury, diabetic kidney disease, and polycystic kidney disease. Understanding these mechanisms may help in identifying new therapeutic strategies targeting AQPs in renal pathologies.

Mycobacterium tuberculosis (MTB) is the etiologic agent of tuberculosis (TB) in humans, an infectious disease that continues to be a significant global health concern. The long-term use of multiple anti-tubercular agents may result in patient non-compliance and increased drug toxicity, which could contribute to the emergence of drug-resistant MTB strains that are not susceptible even to second-line available drugs. It is therefore imperative that new antitubercular drugs and vaccines are developed. The peculiar traits of MTB, such as the biochemical and structural features of vital metabolic pathways, can be assessed to identify possible targets for drug development. Enzymes involved in pyrimidine metabolism may be suitable drug targets for TB, given that this pathway is essential for mycobacteria and comprises enzymes that differ from those found in humans. Here, we focused on reviewing the state of the art concerning the therapeutic opportunities presented by the pyrimidine biosynthetic pathway (PBP) as a potential source of enzymes that could be targeted for the treatment of TB. We selected essential enzymes belonging to the PBP for which we identified the existence of a drug discovery pipeline at both the preclinical and clinical levels. Moreover, we emphasize the biochemical and structural characteristics that are pertinent to the development of pharmaceutical agents. These include the molecular details that can ensure selectivity towards the pathogen's proteins.

Src homology 2 (SH2) domain-containing phosphatase-2 (SHP2, PTPN11) is implicated in diseases such as cancer and RASopathies, where it is often mutated. It has gained strong attention due to promising new drug development strategies, with drug candidates currently in clinical trials. SHP2 is activated downstream of cell surface receptors to promote signaling pathways involved in cell growth and to inhibit immune cell activation. The phosphatase has two SH2 domains and a protein tyrosine phosphatase (PTP) domain, is post-translationally modified, and can function as an active phosphatase or as an adaptor/scaffold protein. It is subject to tight regulation in its cellular environment, for which novel insights have recently emerged. In this focused review, we first summarize the roles of the two SH2 domains and phosphorylation on the regulation of wildtype SHP2. We then describe new developments concerning catalytic and non-catalytic functions of SHP2, as well as recent progress in the understanding of SHP2 regulation, including it being subjected to SUMOylation, activated independently of cell surface receptors, and regulated by substrate phosphorylation. These new insights not only demonstrate the complexity of SHP2 regulation but also guide future studies, contributing important insights that could aid in targeting SHP2 in different disease contexts in the future.

Artificial intelligence (AI) has become a transformative tool in cell biology, driving discoveries through the analysis of complex biological data. This review explores the diverse applications of AI, including its impact on microscopy, imaging, drug discovery, and synthetic biology. AI methods have significantly advanced our ability to analyze cellular images at single-cell resolution, uncover complex patterns in biological data, and predict cellular responses to various stimuli. Deep learning approaches have improved cell segmentation and tracking, facilitated precise single-cell transcriptomics analysis, and enhanced our understanding of protein structures and interactions. The application of AI to high-throughput technologies has also enabled detailed modeling of cell behavior. Key challenges are addressed, such as data quality requirements, model interpretability, and the need to democratize AI tools for broader accessibility in biology. Finally, the review considers future directions, highlighting AI's potential to advance basic research and therapeutic applications.

The biorientation-defective (BOD) protein family, comprising BOD1, BOD1L1 (BOD1-like 1), and BOD1L2, plays critical and diverse roles in fundamental cellular processes, including mitosis, DNA repair, neurological function, and metabolism. BOD1 and BOD1L2 are small proteins of less than 200 amino acids, whereas BOD1L1 contains a long C-terminal extension, totaling 3042 amino acids. BOD1 was originally identified in Xenopus laevis oocyte chromatin extracts. Subsequent work in mitotic human cells demonstrated that BOD1 is an outer kinetochore protein that regulates PP2A-B56 phosphatase function and consequently is vital for chromosome biorientation and segregation fidelity, hence the name. BOD1 also has important roles in neurological function and lipid metabolism as a component of the COMPASS (complex of proteins associated with SET1)-SETD1B complex. In contrast, BOD1L1 was first identified as a phosphorylated target of the ATM kinase and then highlighted in a screen for DNA replication fork components. Further work demonstrated a role for BOD1L1 in DNA double-stranded break repair, where BOD1L1 is required to recruit the protein RIF1 to damaged chromatin to enable efficient DNA repair and control sensitivity to radio/chemotherapeutics. Consistently, BOD1L1 binds known DNA damage/repair/replication proteins, including FANCD2, RIF1, and BRCA2. Loss of BOD1L1 causes catastrophic genome instability through misrepair and/or overprocessing of damaged DNA. Recently, BOD1L1 has also been shown to regulate the PP2A-B56 phosphatase at kinetochores in mitotic human cells. In contrast, little is known about BOD1L2, which is only expressed in sperm cells and precursors. In this review, we describe recent progress in understanding the functions of this protein family and discuss future avenues of research.