Biochemical Society Transactions[JOURNAL]
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200 papers
A phase separation hypothesis for the biological function of PrP: the role of multivalent interactions at the plasma membrane.
Freire MH, Linden R, Cordeiro Y
Biochem Soc Trans · 2026 Jan · PMID 41608769 · Full text
Although the prion protein (PrP) is well established as the etiological agent of transmissible spongiform encephalopathies, its biological function remains under debate. Native, cellular PrP (PrPC) is a glycosylphosphati...
Although the prion protein (PrP) is well established as the etiological agent of transmissible spongiform encephalopathies, its biological function remains under debate. Native, cellular PrP (PrPC) is a glycosylphosphatidylinositol-anchored protein that interacts with various proteins and other molecular ligands at the cell surface, triggering diverse cellular responses such as neuritogenesis and neuroprotection. PrPC has been proposed to act as a scaffolding protein, facilitating the assembly of multicomponent complexes at the membrane, with signal transduction occurring through the recruitment of transmembrane proteins. Recent findings demonstrate that PrP undergoes phase separation (PS) in vitro and in cellulo, mostly driven by its multivalency, intrinsically disordered N-terminal domain, and ability to bind polyanions. Considering recent data showing that membrane multicomponent complexes may assemble through PS, we discuss the possible formation of biomolecular condensates containing PrP at the membrane in light of previously described PrP protein ligands. In this mini-review, we examine PrP's interactions with key ligands such as epidermal growth factor receptor, apolipoprotein E, amyloid β oligomers, α-synuclein, N-methyl-D-aspartate receptor, postsynaptic density protein 95, integrin β1, and tau, assessing their relevance in PS-mediated condensate formation. These proteins were selected based on their direct or indirect interaction with PrP, biological effects, presence in a membrane environment, and evidence of participation in biomolecular condensates. Based on current evidence, we propose that PS may be a fundamental mechanism underlying PrP's biological role in the membrane.
Lipids regulate epidermal growth factor receptor activation by its ligands.
Hutchison JM, Lemmon MA
Biochem Soc Trans · 2026 Jan · PMID 41569525 · Full text
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...
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.
Loop dynamics, allostery, and function in protein tyrosine phosphatases: insights from molecular simulations.
Welsh CL, Kamerlin SCL
Biochem Soc Trans · 2026 Jan · PMID 41562625 · Full text
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 r...
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.
Targeting opportunities presented by the pyrimidine biosynthesis pathway in Mycobacterium tuberculosis: a brief review.
Alberti M, Miggiano R
Biochem Soc Trans · 2026 Jan · PMID 41527724 · Full text
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...
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.
Regulation of renal aquaporins: implications in tubular epithelial integrity.
Venkatesan V, Sørensen CM, Olesen ETB
Biochem Soc Trans · 2026 Jan · PMID 41527718 · Full text
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 t...
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.
Regulation and activity of the phosphatase SHP2: SH2 domains, dephosphorylation activity, and beyond.
Pierotti CL, Köhn M
Biochem Soc Trans · 2026 Jan · PMID 41510638 · Full text
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 developmen...
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.
Leveraging AI for cell biology discovery.
Simizo A, de Morais M, Vesco M … +1 more , Nakaya H
Biochem Soc Trans · 2026 Jan · PMID 41502213 · Full text
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 impac...
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.
eIF3: a critical player in mRNA recruitment to the ribosome with emerging roles across translation.
Ide NA, Noorwez S, Xu C … +1 more , Aitken CE
Biochem Soc Trans · 2025 Dec · PMID 41441844 · Full text
Eukaryotic translation initiation factor (eIF) 3 is a multi-subunit protein complex that plays critical roles throughout translation initiation and has been implicated in a variety of human diseases. More recently, eIF3...
Eukaryotic translation initiation factor (eIF) 3 is a multi-subunit protein complex that plays critical roles throughout translation initiation and has been implicated in a variety of human diseases. More recently, eIF3 has been tied to translation elongation and termination, as well as translational regulation. And yet, a mechanistic understanding of how eIF3 and its constituent subunits perform their canonical roles during initiation continues to elude us. Work across the last two decades has delineated broad mechanistic roles for some of these subunits and identified distinct modules of the complex that contribute differentially to the recruitment of messenger RNA (mRNA) to the ribosome during initiation. Structural approaches have further illuminated these putative roles. And yet, key mechanistic questions tied to fundamental technical challenges remain. Even so, new developments are poised to address these challenges and push our understanding of eIF3 function forward in the coming years.
Heparan sulphate and neural development: dissecting the roles of astrocyte-expressed heparan sulphate.
Gyimesi M, Okolicsanyi RK, Haupt LM
Biochem Soc Trans · 2025 Dec · PMID 41441843 · Full text
Astrocytes are key regulators of neurogenesis, synaptogenesis, synaptic transmission and the clearance of pathological factors within the brain, while maintaining homeostasis throughout life. They also aid in the establi...
Astrocytes are key regulators of neurogenesis, synaptogenesis, synaptic transmission and the clearance of pathological factors within the brain, while maintaining homeostasis throughout life. They also aid in the establishment and maintenance of a neurogenic niche enriched with precisely balanced growth factors, morphogens and extracellular matrix proteoglycans (PGs) to support neuronal development and function. Membrane-bound heparan sulphate (HS) PGs consist of core proteins decorated with HS glycosaminoglycan side chains, whose highly variable sulphation patterns regulate cellular signalling pathways such as Wnt and fibroblast growth factor. However, the specific contributions of astrocyte-derived and/or neuronal HSPGs within this microenvironment remain unclear. This mini-review examined our current understanding of the regulatory role of astrocyte-expressed HSPGs and their associated HS side chain structural variability. In particular, their influence on prenatal brain development, ageing and the changes occurring that contribute to neurodegeneration. We focused on the emerging concept that HS aggregation and impaired neurogenesis may serve as important preclinical contributors to Alzheimer's disease pathology. Alterations in astrocyteexpressed HS and their HSPG landscape are discussed as potential precursors to pathological HS aggregation and reactivity, shifting the focus of disease initiation to the potential compromise of the supportive astrocytic environment. We suggest that neuronal dysfunction cannot be solely attributed to neurodegeneration but must also be considered in the context of a deteriorating support system, where cells that once nurtured neurogenesis and synaptic integrity become dysfunctional contributors to disease pathology.
Force writes memory: proline isomerization as a molecular memory switch.
Popa I, Berkovich R
Biochem Soc Trans · 2025 Dec · PMID 41437571 · Full text
Mechanical forces play a pivotal role in cellular processes, acting as molecular switches that encode, store, and retrieve information, thereby facilitating a form of molecular memory. This review explores how protein un...
Mechanical forces play a pivotal role in cellular processes, acting as molecular switches that encode, store, and retrieve information, thereby facilitating a form of molecular memory. This review explores how protein unfolding and refolding under tensile loads generate history-dependent responses that regulate domain stability and function. We focus on proline isomerization as a reversible switch, enabling distinct quasi-stable states that underpin medium- to long-term mechanical memory. Leveraging insights from molecular dynamics simulations and experimental data, we propose that proline isomerization creates a graded, adaptive memory response, distinct from binary on-off switches, with implications for biomaterial design and biorobotics. This mechanism offers a framework for developing force-responsive materials with memory properties, enhancing applications in tissue engineering and soft robotics.
A busy BOD1-y: the diverse functions of an intracellular signaling regulatory protein family.
Kucharski TJ, Higgs MR, Compton DA … +1 more , Bechstedt S
Biochem Soc Trans · 2025 Dec · PMID 41417274 · Full text
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 functio...
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.
Catalytic-independent roles of chromatin modifiers in mammalian development and the implications for treating human disease.
Vanyai HK, Blewitt ME
Biochem Soc Trans · 2025 Dec · PMID 41416925 · Full text
The molecular function of chromatin modifiers is canonically assumed to be directly related to their enzymatic activities and these activities are typically measured when investigating the molecular consequences of manip...
The molecular function of chromatin modifiers is canonically assumed to be directly related to their enzymatic activities and these activities are typically measured when investigating the molecular consequences of manipulation in model systems. However, it is increasingly apparent that chromatin modifiers exhibit various functions beyond purely their enzymatic roles and, surprisingly, this is true across many classes of so-called 'writers' and 'erasers', including histone acetylases and methylases, and histone deacetylases and demethylases. Some of the most striking examples of the catalytic-independent roles of chromatin modifiers can be demonstrated in mouse models, where catalytic-inactive-encoding mutant alleles, in contrast with null alleles, can prolong survival during embryogenesis or, even more profoundly, allow otherwise embryonic lethal mutants to be born and live into adulthood. A deep understanding of the enzymatic and non-enzymatic roles of chromatin regulators is of clear relevance to understanding how they contribute to normal biology and becomes even more relevant given that many of these factors are also now therapeutic targets in the context of disease. Since therapeutic options have expanded beyond small molecule enzymatic inhibitors to include degraders and interaction blocking modalities, the time is ripe to consider these questions. In this review, we explore the catalytic-independent functions of members of four classes of chromatin modifiers, through the lens of mouse embryogenesis where much of the limited in vivo data have been reported to date. In addition, we examine how existing mouse models can be assessed to tease apart enzymatic versus non-enzymatic requirements of chromatin modifiers.
Cell fusion in osteoclastogenesis.
Chernomordik LV, Melikov K
Biochem Soc Trans · 2025 Dec · PMID 41416904 · Full text
Multinucleated osteoclasts, generated by fusion of mononucleated precursors, play an essential role in the lifelong remodeling of our bones. Since within the physiological range of osteoclast sizes, their bone-resorbing...
Multinucleated osteoclasts, generated by fusion of mononucleated precursors, play an essential role in the lifelong remodeling of our bones. Since within the physiological range of osteoclast sizes, their bone-resorbing activity grows with successive fusion events, both initiation of this fusion reaction and its switch off are tightly controlled. In this review, we discuss the mechanisms and proteins that facilitate and regulate this fusion process. The pathway of membrane rearrangements in osteoclast fusion shares many mechanistic motifs with other physiologically important cell-cell fusion processes, such as the formation of multinucleated skeletal muscle cells. However, the protein machinery involved in catalyzing these rearrangements in osteoclasts is still poorly understood. A better understanding of the mechanism of osteoclast fusion will hopefully lead to more effective approaches for treating skeletal diseases caused by excessive or insufficient bone resorption.
Regulation via compartmentation: adaptive localization of the proteasome under stress.
Ciechanover A, Livneh I
Biochem Soc Trans · 2025 Dec · PMID 41378844 · Full text
Protein degradation by the ubiquitin-proteasome system and autophagy are essential mechanisms that are involved in virtually all cellular activities, and their inadequate function was shown to underlie the pathogenesis o...
Protein degradation by the ubiquitin-proteasome system and autophagy are essential mechanisms that are involved in virtually all cellular activities, and their inadequate function was shown to underlie the pathogenesis of various medical conditions. Much of the study into these proteolytic systems has been focused on the components that facilitate the selective substrate identification and targeting for degradation. Given that most of the specific breakdown of proteins is mediated via their modification by ubiquitin, much research was dedicated to the enzymes which are responsible for substrate recognition and ubiquitination-E3 ubiquitin ligases. In addition to the complexity of substrate recognition and targeting for degradation, the mechanisms governing proteasome function were found to be tightly regulated, including the assembly of the different proteasomal sub-complexes, its different compositions and specialized subtypes such as the immunoproteasome, posttranslational modification of proteasomal subunits, and adaptations in its activity in face of different cellular states and stress conditions. Studies from recent years have highlighted an as-yet unexplored tier of proteasome regulation, namely its subcellular compartmentation and trafficking. Intracellular proteasome shuttling was shown to serve as an essential stress-coping mechanism in tumor cells and is emerging as a potential target for therapeutic interventions.
Towards a phylogenetically informed approach to solving protein-protein interactions.
Lim CS, Mace P, Fineran PC … +1 more , Gardner PP
Biochem Soc Trans · 2025 Dec · PMID 41348431 · Full text
Protein-protein interactions (PPIs) are critical to all cellular activities. Despite having a large number of proteins, cells have spatial and temporal control over PPIs to avoid dysregulation in cellular pathways. Consi...
Protein-protein interactions (PPIs) are critical to all cellular activities. Despite having a large number of proteins, cells have spatial and temporal control over PPIs to avoid dysregulation in cellular pathways. Considerable research efforts have aimed to find new PPIs, curate PPIs from the literature and build searchable PPI databases. These databases have been widely used by experimental and computational scientists. Here we find that the PPIs captured by these databases are highly heterogeneous and concentrated on a small number of species. These issues hamper researchers from capturing the full landscape of reliable PPIs, affecting the accuracy of machine-learning models and the effectiveness of experimental designs. However, there are opportunities to fill gaps computationally and experimentally. We suggest developing a phylogenetically informed approach to test PPIs experimentally and computationally.
Tuft cell-mediated pathogen sensing and inflammation resolution.
Huang L, Peng YY, Yu D
Biochem Soc Trans · 2025 Dec · PMID 41288617 · Full text
Tuft cells are a rare type of epithelial cells characterized not only by their tuft-like structure but also by the expression of specific genes, including those encoding the transcription factor Pou2f3 and canonical gust...
Tuft cells are a rare type of epithelial cells characterized not only by their tuft-like structure but also by the expression of specific genes, including those encoding the transcription factor Pou2f3 and canonical gustatory signaling proteins. However, tuft cells can be heterogeneous in various features, both across different tissues and within the same tissue. Homeostatic tuft cells are generated from stem/progenitor cells; however, their formation and gene expression profiles are regulated epigenetically and in response to changes in their microenvironments. Ectopic formation of tuft cells, their transdifferentiation into other cell types, and dedifferentiation to stem/progenitor cells have also been found in some tissues upon severe injuries. Tuft cells function as chemosensory sentinels and can detect a variety of pathogens such as bacteria, protists, and helminths with their cell surface receptors. Activation of these receptors in turn activates intracellular signaling cascades, leading to the release of output effectors: the cytokine IL-25, the eicosanoids, and the transmitters acetyl choline and ATP, some of which act on group 2 innate lymphoid cells, triggering innate immune responses, or on neighboring epithelial cells to accelerate cilia beating and increase mucus secretion, or on the nerve terminals to initiate neuroimmune responses. Some tuft cells are also critical to inflammation resolution and tissue repair-an important part of the healing and recovery process. Further elucidation of tuft cells' ligands, respective receptors and downstream signaling pathways, and output effectors can provide more insights into these cells' pivotal roles in health and disease.
Unraveling the interplay of DNA methylation and chromosome organization.
Pei Y, Li G
Biochem Soc Trans · 2025 Dec · PMID 41258729 · Full text
Eukaryotic DNA has been covalently modified by DNA methylation and folded into a three-dimensional conformation in the nucleus. While the functions of DNA methylation and chromosome organization have been widely discusse...
Eukaryotic DNA has been covalently modified by DNA methylation and folded into a three-dimensional conformation in the nucleus. While the functions of DNA methylation and chromosome organization have been widely discussed, respectively, the interplay between DNA methylation and chromosome organization remains less clear and needs to be further explained. In this review, we first discuss the cross-talk between DNA methylation and chromosome conformation, highlighting the complexity and importance of DNA methylation on chromosome organization. We also summarize the current methodologies that capture DNA methylation and chromosome organization individually or simultaneously in bulk and single cells. These mechanistic and methodological advancements facilitate broad interest in unveiling the interplay between DNA methylation and chromosome organization.
Navigating lipid droplet proteins - part I: ER targeting routes of lipid droplet-destined membrane proteins.
Krauß LM, Schrul B
Biochem Soc Trans · 2025 Oct · PMID 41160907 · Full text
Lipid droplets (LDs) are cytosolic lipid storage organelles that derive from the endoplasmic reticulum (ER). Their biogenesis and function are essential for maintaining cellular lipid homeostasis and require a spatiotemp...
Lipid droplets (LDs) are cytosolic lipid storage organelles that derive from the endoplasmic reticulum (ER). Their biogenesis and function are essential for maintaining cellular lipid homeostasis and require a spatiotemporally co-ordinated recruitment of specific membrane proteins to the LD surface. Many LD-destined proteins are inserted into the ER phospholipid bilayer in a monotopic hairpin topology before they can partition to the LD monolayer. About a third of all cellular proteins enter the ER during their biogenesis, either as ER-resident or as secretory proteins. Decades of research have provided a solid understanding of which molecular machineries ensure ER targeting fidelity of transmembrane-spanning proteins. The molecular mechanisms underlying the biogenesis of LD-destined monotopic proteins, however, are only beginning to emerge. In this first part of the bipartite review 'Navigating lipid droplet proteins,' we provide an overview of the general principles underlying protein targeting to the ER. We highlight recent advances and current challenges regarding the specific mechanisms for LD-destined proteins and discuss their physiological implications. The molecular mechanisms underlying the subsequent ER-to-LD protein partitioning are at the heart of the second part of this bipartite review.
Navigating lipid droplet proteins - part II: molecular mechanisms underlying ER-to-lipid droplet protein partitioning.
Krauß LM, Schrul B
Biochem Soc Trans · 2025 Oct · PMID 41160906 · Full text
Lipid droplets (LDs) originate from the endoplasmic reticulum (ER) and are unique among cellular organelles, as they consist of a hydrophobic core of neutral lipids that is surrounded by a phospholipid monolayer. Protein...
Lipid droplets (LDs) originate from the endoplasmic reticulum (ER) and are unique among cellular organelles, as they consist of a hydrophobic core of neutral lipids that is surrounded by a phospholipid monolayer. Proteins and enzymes embedded into this monolayer are essential for regulating dynamic lipid storage and consumption and hence, for the cellular adaptation to metabolic changes. Their activity and abundance on the LD surface must therefore be well-controlled. Many of these proteins are first inserted into the phospholipid bilayer membrane of the ER before they partition to the LD monolayer. While a monotopic membrane topology is required for enabling the targeting of these ERTOLD proteins from the ER to LDs, the molecular mechanisms underlying this partitioning are only beginning to emerge. In this second part of the bipartite review 'Navigating lipid droplet proteins,' we discuss recent conceptual advances regarding ER-to-LD protein partitioning and focus on novel insights into the structural dynamics of LD-destined proteins, how their partitioning to LDs is temporally controlled, and the hierarchies involved in selective and competitive protein recruitment to LDs according to metabolic needs and functions.
Chromatin insulators in gene regulation and 3D genome organization.
Sultana H, Kunar R, Matera AG
Biochem Soc Trans · 2025 Oct · PMID 41151055 · Full text
The human genome attains an amazing spatial organization in the packaging of 2 m of DNA into a 10-μm nucleus. Such structural organization is achieved by the folding of chromatin and the regulation exerted by architectur...
The human genome attains an amazing spatial organization in the packaging of 2 m of DNA into a 10-μm nucleus. Such structural organization is achieved by the folding of chromatin and the regulation exerted by architectural proteins such as insulators. Chromatin insulators are boundary elements of the genome that, through enhancing blocking activities, demarcation of chromatin domains, and chromatin looping, regulate transcription. The review focuses on the identification and characterization of insulators in various species, discussing mainly the functions of the CCCTC-binding factor (CTCF) in mammals and functionally equivalent insulator proteins in Drosophila melanogaster. We review here the mechanisms of enhancer blocking, barrier activity, and loop extrusion, emphasizing their effects on topologically associating domains and chromatin architecture. Furthermore, we discuss new concepts that have come into prominence: tethering elements and redundancy among the insulator proteins, which contribute to chromatin organization. Advances in methodology, including chromosome conformation capture and high-resolution imaging techniques, have transformed our view of the dynamic interplay between the architecture of chromatin and transcription regulation. This review discusses the importance of insulators for genome organization and describes future directions in investigating their roles in both gene regulation and three-dimensional genomic architecture.
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