Biochemical Society Transactions[JOURNAL]
Sun
200 papers
Engineering protein prenylation: an emerging tool for selective protein modification.
Venkatachalapathy S, Lichtenfels C, Wagner CR … +1 more , Distefano MD
Biochem Soc Trans · 2025 Aug · PMID 40879408 · Full text
Prenyltransferases catalyze the attachment of isoprenoids to cysteine residues located near the C-termini of proteins including those containing a 'CaaX' tetrapeptide motif. This enzyme family includes farnesyl transfera...
Prenyltransferases catalyze the attachment of isoprenoids to cysteine residues located near the C-termini of proteins including those containing a 'CaaX' tetrapeptide motif. This enzyme family includes farnesyl transferase (FTase), geranylgeranyltransferase type I (GGTase I), and GGTase type II (GGTase II). The CaaX motif broadly consists of cysteine (C), two aliphatic residues (a), and a variable residue (X), which determines substrate specificity for farnesylation and type I geranylgeranylation. This review primarily focuses on FTase-mediated protein modification strategies for assembling therapeutically valuable proteins. First, the process of protein prenylation and the structural features of the FTase active site are discussed. This is followed by an exploration of FTase-catalyzed bioconjugation of monomeric proteins and peptides, emphasizing its efficiency, modularity, and potential for industrial biological applications. The broader applicability of this approach is then highlighted in the design and assembly of multimeric protein structures, facilitating the development of complex biomolecular architectures with enhanced functionality, stability, and therapeutic potential. Finally, FTase mutagenesis strategies are examined that expand substrate scope, accommodating diverse functional groups for a wide range of biotechnological and therapeutic applications.
Translation stalling in neurons: a critical mechanism for timely protein delivery to distal cellular processes.
Sun J, Drever L, Ortega J … +1 more , Sossin WS
Biochem Soc Trans · 2025 Aug · PMID 40857743 · Full text
Neurons require local protein synthesis at synapses to control their proteome in response to local inputs. Work over the past two decades has revealed that neurons can use a specialized mechanism to transfer mRNAs and ri...
Neurons require local protein synthesis at synapses to control their proteome in response to local inputs. Work over the past two decades has revealed that neurons can use a specialized mechanism to transfer mRNAs and ribosomes to local sites in addition to canonical mechanisms used in many cell types. Neurons initiate translation on the ribosomes in the cellular soma, pause the process, and then package these stalled ribosomes into structures known as 'neuronal RNA granules' that are transported to synapses. This review provides an overview of recent studies that characterize these ribosomes/granules biochemically and structurally. These studies provide novel insights into the unique and specialized characteristics of neuronal ribosomes that facilitate this distinct transport mechanism. Many questions remain, including the influence of mRNA sequences on the stalling process and how ribosomes in the granules avoid the physiological responses that, in other cells, recycle ribosomal subunits upon stalling. Many neurodevelopmental disorders, such as autism and intellectual disability, occur when local translation is disrupted in neurons. Understanding mechanisms underlying the stalling of neuronal ribosomes, their transport to processes, and their reactivation may enable novel therapies for neurodevelopmental diseases.
Regulation of early gonocyte differentiation in zebrafish.
Wilson ML, Marlow FL
Biochem Soc Trans · 2025 Aug · PMID 40857739 · Full text
Zebrafish have been and continue to be an important model organism for studies of fundamental biology and biomedicine, including reproductive development and the cell intrinsic and extrinsic mechanisms regulating early g...
Zebrafish have been and continue to be an important model organism for studies of fundamental biology and biomedicine, including reproductive development and the cell intrinsic and extrinsic mechanisms regulating early gonocyte differentiation. Wild zebrafish strains determine sex using a ZW genetic system wherein the maternally inherited sex chromosome determines the embryo's sex. Like other species, including humans, regulation of conserved autosomal genes is crucial for gonocyte and sexual differentiation. How these conserved factors are regulated by the diverse mechanisms found throughout the animal kingdom is an active area of investigation. Domesticated zebrafish strains lack the ZW sex determination system found in wild strains and undergo gonocyte and sexual differentiation through a process exclusively governed by autosomal genes and nongenetic influences like environmental factors. Through mutational analysis, molecular genetics, and RNA sequencing, our understanding of the complexity of oocyte and spermatocyte differentiation has become clearer. In this review, we explore the most recent studies of the conserved and divergent mechanisms of gonocyte differentiation between wild and domesticated zebrafish as well as possible adaptations related to their domestication. Further, the contributions of individual genes and their molecular genetic hierarchy in regulating gonocyte differentiation are discussed and related to other species where relevant. We also address the recent characterization of a novel oocyte-progenitor and its potential implications in gonad differentiation. Finally, the role of gonocyte-extrinsic mechanisms, specifically communication between differentiating gonocytes and surrounding somatic gonad cells and the influence of resident and infiltrating immune cells, is discussed.
Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.
Baker MJ, Yek KQ, Stojanovski D
Biochem Soc Trans · 2025 Aug · PMID 40857737 · Full text
Intrinsic protein quality control (QC) mechanisms are essential in maintaining mitochondrial health and function. These sophisticated molecular machineries govern protein trafficking and import, processing, folding, matu...
Intrinsic protein quality control (QC) mechanisms are essential in maintaining mitochondrial health and function. These sophisticated molecular machineries govern protein trafficking and import, processing, folding, maturation and degradation, ensuring the organelle's health. Disruption in mitochondrial protein QC can lead to severe, multisystem disorders with variable age of onset and progression. In this review, we provide a snapshot of the intrinsic molecular protein QC machineries in mitochondria detailing their function, localisation and substrate specificity. We also highlight how dysfunction of these molecular machines contributes to mitochondrial disease. Ultimately, elucidating the consequences of proteostatic failure offers critical insights into the pathogenesis of complex mitochondrial disorders.
Multifaceted roles of mycobacterial HflX: ribosome splitting, rRNA disordering, and drug resistance.
Majumdar S, Ghosh P, Agrawal RK
Biochem Soc Trans · 2025 Aug · PMID 40833115 · Full text
High frequency of lysogenization X (HflX) is an enigmatic protein that has been implicated in rescuing translationally stalled ribosomes and macrolide-lincosamide antibiotic resistance, as well as in ribosome biogenesis....
High frequency of lysogenization X (HflX) is an enigmatic protein that has been implicated in rescuing translationally stalled ribosomes and macrolide-lincosamide antibiotic resistance, as well as in ribosome biogenesis. The protein shows significant sequence and structural variation across species, including variation among paralogs within the same organism. Recent cryo-EM structure determination of ribosome-HflX complexes from different eubacterial species has provided important mechanistic clues to HflX function. Mycobacterial HflXs carry a distinct N-terminal extension (NTE) and a small insertion, as compared with their eubacterial homologs, suggesting that the mycobacterial HflX could have distinct functional mechanisms. This article presents a brief overview of these studies highlighting (i) what we have learned from recent multiple mycobacterial ribosome-HflX complex structures and (ii) the roles of mycobacteria-specific segments in ribosomal RNA disordering that leads to ribosome splitting to rescue translation by removing the drug-bound stalled ribosome from the translationally active polysome pool. Future studies needed to resolve some of the outstanding issues related to HflX function and dynamics are also discussed.
Mechanisms of fusidic acid resistance.
González-López A, Selmer M
Biochem Soc Trans · 2025 Aug · PMID 40827472 · Full text
Fusidic acid (FA) is an antibiotic used to treat staphylococcal infections, particularly Staphylococcus aureus. It acts by inhibiting protein synthesis through locking elongation factor G (EF-G) to the ribosome. In S. au...
Fusidic acid (FA) is an antibiotic used to treat staphylococcal infections, particularly Staphylococcus aureus. It acts by inhibiting protein synthesis through locking elongation factor G (EF-G) to the ribosome. In S. aureus, there are three mechanisms of resistance. Mutations in the antibiotic target, EF-G (fusA), are common. These mutations affect the FA binding or the stability of the FA-locked state of EF-G but, due to effects on the normal function of EF-G, impose a fitness cost for the pathogen. The most common mechanism, FusB-type, involves expression of a resistance protein, FusB or FusC (FusD or FusF in other staphylococci), that provides target protection. The resistance protein binds to EF-G in its FA-locked state and mediates its release from the ribosome. An uncommon resistance mechanism (FusE) involves mutations in a ribosomal protein, uL6. In other bacteria, outside of its current clinical use, resistance to FA involves efflux pumps, limited membrane permeability, or enzymes that chemically alter FA. On a global level, the prevalence of FA resistance is relatively low, indicating that the antibiotic remains effective.
Canonical and alternate mechanisms that regulate ubiquitylation by the E3 ligase parkin.
Basilone NT, Pimenta VM, Shaw GS
Biochem Soc Trans · 2025 Aug · PMID 40827359 · Full text
Parkin, a Ring-InBetweenRING-Rcat E3 ubiquitin ligase, plays a vital role in the clearance of damaged mitochondria (mitophagy) by ubiquitylating a broad spectrum of mitochondrial proteins. Mutations in the PRKN gene alte...
Parkin, a Ring-InBetweenRING-Rcat E3 ubiquitin ligase, plays a vital role in the clearance of damaged mitochondria (mitophagy) by ubiquitylating a broad spectrum of mitochondrial proteins. Mutations in the PRKN gene alter parkin ubiquitylation activity and are a leading cause of early-onset Parkinsonism, underlining its critical function in maintaining mitochondrial homeostasis. The structures, substrates, and ubiquitylation mechanisms used by parkin in mitophagy are well established. Yet, early studies as well as more recent proteomics studies identify alternative substrates that reside in the cytosol or other cellular compartments, suggesting potential roles for parkin beyond mitophagy. In addition to its well-documented activation via S65 phosphorylation, numerous other post-translational modifications (PTMs) have been identified in parkin. Some of these modifications have the potential to serve key regulatory mechanisms, perhaps fine-tuning parkin activity or potentially signaling the involvement in alternative cellular pathways beyond mitochondrial quality control. This review examines the canonical mechanism of parkin-mediated ubiquitylation while also exploring alternative regulatory influences that may modulate its enzyme activity. By analyzing emerging evidence on PTMs including phosphorylation, acetylation, ubiquitylation, oxidation, and interaction with alternative activating molecules, we highlight the broader functional landscape of parkin and its implications for cellular stress response.
Control of epithelial homeostasis by apical polarity: it takes a network.
Lelièvre SA, Briand J
Biochem Soc Trans · 2025 Aug · PMID 40827349 · Full text
The maintenance of cell functions in response to various stimuli is fulfilled by tightly controlled homeostatic processes. The basoapical structure of normal epithelia is increasingly recognized as the guardian of homeos...
The maintenance of cell functions in response to various stimuli is fulfilled by tightly controlled homeostatic processes. The basoapical structure of normal epithelia is increasingly recognized as the guardian of homeostasis. It has recently been demonstrated that apical polarity, depicted by lateroapical tight junctions, is controlled by gap junctions and sets the resting membrane potential, itself essential for homeostasis, in the breast luminal epithelium. In the breast, the disruption of apical polarity is recognized as a necessary step toward cancer onset, which calls for a better understanding of its consequences on the mechanisms of homeostasis all the way to the genome. Here, we extend the traditional apical junctional complex to include gap junctions and investigate its relation with epigenetically- driven and higher order chromatin organization. The disruption of apical polarity affects different types of molecular networks that remodel chromatin with a tendency toward openness or relaxation, a status typically associated with instability and cancer onset. Events known to foster the development of cancers, such as chronic inflammation, oxidative stress, stiffer microenvironment, and aging, are all triggering the disruption of apical polarity, which leads us to explore possibilities to re-establish full polarity. Focusing on gap junction intercellular communication mediated by Connexin 43 might be an interesting therapeutic option for retinoic acid derivatives. However, in light of the different degrees of apical polarity loss, we surmise that the resulting chromatin alterations might depend on the way apical polarity is disrupted initially, which suggests that therapeutic combinations targeted also toward these alterations might be required.
The exit from naive pluripotency: a platform for the study of enhancer mechanistics.
Jonasson ME, Buecker C
Biochem Soc Trans · 2025 Aug · PMID 40827347 · Full text
Multicellular life depends on the ability to activate and repress genes in a highly context-specific manner. With each cell state transition, a new transcriptional profile is established. As non-coding DNA elements, enha...
Multicellular life depends on the ability to activate and repress genes in a highly context-specific manner. With each cell state transition, a new transcriptional profile is established. As non-coding DNA elements, enhancers mediate their regulatory potential through the effectors they recruit. While ultimately instructed by the underlying DNA sequence, enhancer activity depends on several factors, such as transcription factor availability, chromatin state, and promoter proximity, all of which are dynamically regulated within the cell. Even when we understand the regulation of one enhancer, its genomic impact is dependent on its integration within the regulatory landscape. Thus, a full picture of enhancer dynamics can only be painted through broad, but controlled, approaches that integrate investigations into multiple levels of gene regulatory mechanisms. In this review, we will present the exit of naive pluripotency as a prime setting to do just that and contextualize how its contemporary use has been, and could be, used to reveal the intricacies of enhancer mechanistics.
RAS-membrane interaction and oligomerization: there is more than meets the eye.
Sianoya AC, Bhardwaj VK, Gorfe AA
Biochem Soc Trans · 2025 Aug · PMID 40801144 · Full text
Membrane association is fundamental to Rat sarcoma (RAS) function, driving both its physiologic signaling and oncogenic transformation. This review consolidates recent advances in the study of RAS-membrane interactions,...
Membrane association is fundamental to Rat sarcoma (RAS) function, driving both its physiologic signaling and oncogenic transformation. This review consolidates recent advances in the study of RAS-membrane interactions, emphasizing the molecular mechanisms underlying its membrane engagement and oligomerization. We first discuss the roles of RAS lipid modification and conformational diversity of its intrinsically disordered C-terminus in these processes, and we then examine the debate surrounding RAS dimerization and its potential role in the formation of higher-order oligomers. By integrating emerging insights into these issues, we offer our own perspectives on the driving forces of RAS oligomerization and propose potential new avenues for developing targeted therapies for RAS-driven cancers.
Emerging drivers of DNA repeat expansions.
Li L, Scott WS, Mirkin SM
Biochem Soc Trans · 2025 Aug · PMID 40801134 · Full text
Expansions of short tandem repeats (STRs) are the cause of a class of human hereditary disorders called repeat expansion diseases (REDs). Most REDs are neurodegenerative or neurodevelopmental diseases such as Huntington'...
Expansions of short tandem repeats (STRs) are the cause of a class of human hereditary disorders called repeat expansion diseases (REDs). Most REDs are neurodegenerative or neurodevelopmental diseases such as Huntington's disease, myotonic dystrophy, fragile X syndrome, and Friedreich's ataxia. Some common neurodegenerative diseases, including Alzheimer's and Parkinson's disease, have also been associated with STR expansions. Many cellular processes such as meiotic recombination, DNA replication, and mismatch repair have been shown to promote STR instability. However, STR instability is likely the result of a variety of factors, and many questions regarding this phenomenon remain to be answered. In this review, we summarize recent studies that propose DNA single-strand breaks as drivers of large-scale STR instability, in both dividing and non-dividing cells, and discuss additional evidence that supports this model. We also highlight the FANCD2- and FANCI-associated nuclease 1 protein, which was shown to be the strongest genetic modifier of several REDs.
Should I stay or should I go: TFIIIC as assembly factor and barrier in RNA polymerase III transcription.
Seifert-Davila W, van Breugel ME, van Leeuwen F … +1 more , Müller CW
Biochem Soc Trans · 2025 Aug · PMID 40762516 · Full text
Critical for the regulation of eukaryotic gene transcription is the assembly and interplay of general transcription factors (GTFs) with RNA polymerases (RNAPs), leading to the formation of pre-initiation complexes (PICs)...
Critical for the regulation of eukaryotic gene transcription is the assembly and interplay of general transcription factors (GTFs) with RNA polymerases (RNAPs), leading to the formation of pre-initiation complexes (PICs) as a rate-limiting step in transcription activation. Compared with RNAPII PIC assembly involving many GTFs, activators, and co-activators, RNAPIII PIC assembly is less complex, involving mainly the four GTFs TFIIIA, TFIIIB, TFIIIC, and snRNA activating protein complex with only a few additional factors. The RNAPIII-specific GTF TFIIIC is present in type I and II promoters. One prominent area of investigation has been the dynamic interaction between TFIIIC and its promoter elements, the varying affinities of TFIIIC toward these elements, and the flexible linker within TFIIIC. Additionally, evidence suggests that TFIIIC may play a dual role, acting as an assembly factor that positions TFIIIB during PIC formation and as a barrier during RNAPIII-mediated transcription. By summarizing recent structural, biochemical, and genomic data, this review explores the mechanisms by which RNAPIII-specific GTFs, with a focus on TFIIIC, dynamically regulate RNAPIII transcription.
The states of senescent cells.
de Mendonça LB, Lenz G, Filippi-Chiela EC
Biochem Soc Trans · 2025 Aug · PMID 40758278 · Full text
Senescent cells (SnCs) have typical changes in multiple features, such as increased cellular and nuclear size, morphofunctional alterations in organelles, and high secretory activity. The literature generally groups cell...
Senescent cells (SnCs) have typical changes in multiple features, such as increased cellular and nuclear size, morphofunctional alterations in organelles, and high secretory activity. The literature generally groups cellular changes and the non-proliferative character of SnCs into the autonomous senescent phenotype. In contrast, the influence of molecules and extracellular vesicles secreted by SnCs characterizes their non-autonomous phenotype. Unlike the detailed characterization of the structure of SnCs, the discussion regarding SnC states, which are characterized by the comprehensive integration of multiple features a cell harbors in a given moment, is still incipient. This review discusses the possible SnC states (SenStates) and their influence in pathophysiological contexts. We also discuss the main mechanisms and molecular players involved in the establishment and dynamics of these states, such as transcription factors, epigenetic marks, chromatin structure, and others. Finally, we discuss the biological relevance and potential clinical applications of SenStates, as well as open questions in the field.
Temporal dynamics of angiogenesis: the emerging role of mechanoregulated pathways.
Zarin-Bal S, Passier M, Bentley K … +1 more , Ristori T
Biochem Soc Trans · 2025 Aug · PMID 40758194 · Full text
Controlling the formation of new blood vessels, i.e. angiogenesis, is a critical challenge for the success of regenerative medicine. The development of effective strategies is hindered by our incomplete understanding of...
Controlling the formation of new blood vessels, i.e. angiogenesis, is a critical challenge for the success of regenerative medicine. The development of effective strategies is hindered by our incomplete understanding of the dynamic mechanisms involved. During physiological angiogenesis, endothelial cells ensure the formation of a functional vascular network by organizing into phenotypic patterns of tip and stalk cells, as mediated by cell-cell signaling communication. While fundamental research identified the major signaling pathways involved in the tip-stalk selection process, recent studies have highlighted the importance of the temporal dynamics of these signaling pathways in determining the final vascular network topology. In this review, we discuss research studies where synergistic approaches between experimental and computational methods led to a renovated understanding of angiogenesis by revealing new temporal regulators of tip-stalk selection. Next, we present increasing evidence suggesting that mechanical cues, such as extracellular matrix stiffness, cyclic strain, and shear stress, are potential temporal regulators of the dynamics of tip-stalk selection and angiogenesis. Future research focused on this promising direction could enable the development of novel approaches that leverage temporal variations of mechanical cues to steer blood vessel growth.
Anticancer drug development against ribosome synthesis and the nucleolus.
Loiacono A, Huang S
Biochem Soc Trans · 2025 Aug · PMID 40758167 · Full text
Nucleoli, the most prominent nuclear organelle, form around ribosomal DNA (rDNA) clusters at the p-arms of the five acrocentric chromosomes. Nucleoli are centers of ribosome synthesis, a vital activity in cell proliferat...
Nucleoli, the most prominent nuclear organelle, form around ribosomal DNA (rDNA) clusters at the p-arms of the five acrocentric chromosomes. Nucleoli are centers of ribosome synthesis, a vital activity in cell proliferation and organism viability. Ribosome biogenesis is a complex process involving the activity of all three RNA polymerases and numerous cellular factors. This energy-consuming process is, therefore, highly regulated, with the transcription of rDNA being the rate-limiting step. Given that uncontrolled cell proliferation is a hallmark of cancer, enhanced ribosome biogenesis plays a crucial role in sustaining tumor growth. In addition, nucleoli are multi-functional organelles, participating in genome organization, cell cycle, stress sensing, macromolecular trafficking, and the sequestration of cellular factors-functions that are also significantly altered in cancerous conditions. This review focuses on summarizing the role of nucleoli in carcinogenesis and anticancer therapeutics that target nucleoli and ribosome synthesis.
Redesigning miR-34a: structural and chemical advances in the therapeutic development of an miRNA anti-cancer agent.
Iyer SG, Sohal IS, Kasinski AL
Biochem Soc Trans · 2025 Aug · PMID 40758119 · Full text
MicroRNAs (miRNAs) represent a promising class of therapeutics due to their ability to down-regulate multiple genes simultaneously. This offers a significant therapeutic advantage in cancer, where heterogeneity often act...
MicroRNAs (miRNAs) represent a promising class of therapeutics due to their ability to down-regulate multiple genes simultaneously. This offers a significant therapeutic advantage in cancer, where heterogeneity often activates different pathways in different patients. Chemical modifications to the miRNA help overcome challenges associated with nuclease susceptibility, high immunogenicity, and the need for high or repeated dosing to achieve therapeutic effects. The main chemical modifications include changes to the ribose and backbone. Ribose modifications, including 2'-O-methyl and 2'-fluoro, improve nuclease resistance and plasma stability and lower the immunogenicity of the miRNA. Phosphorothioate (PS) backbone modifications increase resistance to nucleases and prolong circulation by enhancing serum protein affinity. Integrating these stabilizing chemical modifications with ligand targeting allows for specific delivery of the chemically modified miRNAs to tumors and metastases, bypassing bulky delivery vehicles and improving penetration into dense tumor architectures. Enhancements to ligand chemistry can also overcome endosomal entrapment. Incorporating many of the modifications discussed in this mini-review, the first fully modified version of miR-34a (FM-miR-34a) was developed, marking a significant milestone as the first fully modified miRNA to demonstrate substantial in vivo activity. Ongoing optimization of the chemical modifications and ligand chemistry, and integrating artificial intelligence into the design process are expected to further extend the potential for delivering on the promise of using these Nobel Prize-winning miRNAs as anti-cancer agents.
Disturbances of endoplasmic reticulum proteostasis in neurodevelopmental disorders.
Medinas DB, Pereira N, Pereira R … +2 more , da Silva GR, Santos VHS
Biochem Soc Trans · 2025 Aug · PMID 40719631 · Full text
The endoplasmic reticulum (ER) is a vital organelle involved in the biogenesis of membrane and secreted proteins. Proteostasis (protein homeostasis) in the ER relies on finely co-ordinated mechanisms for translocation of...
The endoplasmic reticulum (ER) is a vital organelle involved in the biogenesis of membrane and secreted proteins. Proteostasis (protein homeostasis) in the ER relies on finely co-ordinated mechanisms for translocation of polypeptides from the cytosol to the organelle lumen and membrane, introduction of co- and post-translational modifications, protein folding and quality control, exportation of mature proteins and disposal of unfolded or aggregated species, besides the regulation of gene expression to adjust the proteostasis network to the cellular demands for protein biogenesis. Neurodevelopmental processes involving neurogenesis, neuronal migration and differentiation, neural circuit wiring, synaptogenesis, among others, require extensive proteome diversification and remodeling, with high fluxes through the secretory pathways constantly challenging ER proteostasis. Genetic defects affecting the different nodes of the ER proteostasis network can severely disturb neurodevelopment. Here, we compile evidence illustrating how perturbations to the different steps of protein biogenesis in the ER can lead to neurological disorders and present major questions to guide research in the field.
How does protein aggregate structure affect mechanisms of disaggregation?
Yang Y, Rye HS
Biochem Soc Trans · 2025 Aug · PMID 40706009 · Full text
Protein misfolding and aggregation underpin numerous pathological conditions, including Alzheimer's, Parkinson's, and Huntington's diseases. Within cells, the competition between protein folding and misfolding-driven agg...
Protein misfolding and aggregation underpin numerous pathological conditions, including Alzheimer's, Parkinson's, and Huntington's diseases. Within cells, the competition between protein folding and misfolding-driven aggregation necessitates intricate quality control systems known collectively as the proteostasis network, with molecular chaperones playing central roles. Critical gaps remain in our understanding of why certain protein aggregates are amenable to efficient chaperone-mediated disassembly, while others resist such intervention. Aggregates can be most broadly categorized into structurally ordered amyloid fibrils and more irregular amorphous clusters. Amyloid fibrils are characterized by a highly structured, cross-β-sheet architecture, and they generally display nucleation-driven growth kinetics. In contrast, amorphous aggregates form through heterogeneous interactions among partially unfolded proteins, which typically lack ordered and repeating structure but still display poorly understood, specific assembly constraints. Importantly, amorphous aggregation and amyloid formation are often linked to one another, with several different types of aggregate structures forming at the same time. The ability of molecular chaperones to remodel and disassemble aggregates is affected by aggregate size, internal structure, surface dynamics, and exposure of chaperone-binding sites. However, despite these insights, the mechanistic complexity, aggregate heterogeneity, and dynamic properties present substantial experimental and theoretical challenges. Addressing these challenges will require innovative approaches combining single-molecule biophysics, structural biology, and computational modeling to unveil universal principles governing protein aggregation and disaggregation within cellular environments.
Advances in mechanochemical modelling of vertebrate gastrulation.
Plum AM, Serra M, Weijer CJ
Biochem Soc Trans · 2025 Jul · PMID 40700026 · Full text
Gastrulation is an essential process in the early embryonic development of all higher animals. During gastrulation, the three embryonic germ layers, the ectoderm, mesoderm and endoderm, form and move to their correct pos...
Gastrulation is an essential process in the early embryonic development of all higher animals. During gastrulation, the three embryonic germ layers, the ectoderm, mesoderm and endoderm, form and move to their correct positions in the developing embryo. This process requires the integration of cell division, differentiation and movement of thousands of cells. These cell behaviours are coordinated through shortand long-range signalling and must involve feedback to execute gastrulation in a reproducible and robust manner. Mechanosensitive signalling pathways and processes are being uncovered, revealing that shortand long-range mechanical stresses integrate cell behaviours at the tissue and organism scale. Because the interactions between cell behaviours, signalling and feedback are complex, combining experimental and modelling approaches is necessary to elucidate the regulatory mechanisms that drive development. We highlight how recent experimental and theoretical studies provided key insights into mechanical feedback that coordinates relevant cell behaviours at the organism scale during gastrulation. We outline advances in modelling the mechanochemical processes controlling primitive streak formation in the early avian embryo and discuss future developments.
Why are imprints unstable in pluripotent stem cells?
Arez M, da Rocha ST
Biochem Soc Trans · 2025 Jul · PMID 40676847 · Full text
Pluripotent stem cells (PSCs) possess the remarkable ability to self-renew and differentiate into nearly any cell type, making them invaluable for both research and therapeutic applications. Despite these powerful attrib...
Pluripotent stem cells (PSCs) possess the remarkable ability to self-renew and differentiate into nearly any cell type, making them invaluable for both research and therapeutic applications. Despite these powerful attributes, PSCs are vulnerable to genetic and epigenetic instabilities that can undermine their reliability and safety. While genetic abnormalities can be routinely monitored with established guidelines, epigenetic instabilities often go unchecked. Among the most recurrent epigenetic defects in PSCs are errors in genomic imprinting - a process that governs parent-of-origin-specific monoallelic expression of certain genes through differential marking of the two parental alleles by DNA methylation. When disrupted, it becomes a source of a dozen developmental conditions known as imprinting diseases. In PSCs, once imprinting errors arise, they remain throughout cellular differentiation, casting uncertainty over the use of PSC-derived cells for disease modelling and regenerative medicine. In this review, we provide an overview of imprinting defects in both mouse and human PSCs, delving into their origins and consequences. We also discuss potential correction strategies that aim to enhance imprinting stability, ultimately paving the way for safer, more reliable PSC use in research and clinical applications.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe