Human glucokinase (GCK) functions as a glucose sensor in the pancreas and liver, where GCK activity regulates insulin secretion and glycogen synthesis, respectively. GCK’s low affinity for glucose and the sigmoidal substrate dependency of enzymatic turnover enables it to act as a sensor that makes cells responsive to changes in circulating glucose levels. Its unusual kinetic properties are intrinsically linked to the enzyme’s conformational dynamics. Accordingly, genetic variants that alter the dynamics or other aspects of GCK function are linked to three glucose homeostasis diseases. In this review, we describe the enzyme GCK, focusing on its role as a glucose sensor, its unusual kinetic properties, and recent large-scale efforts to assess GCK variant effects.
{"title":"Glucokinase: from allosteric glucose sensing to disease variants","authors":"Sarah Gersing , Torben Hansen , Kresten Lindorff-Larsen , Rasmus Hartmann-Petersen","doi":"10.1016/j.tibs.2024.12.007","DOIUrl":"10.1016/j.tibs.2024.12.007","url":null,"abstract":"<div><div>Human glucokinase (GCK) functions as a glucose sensor in the pancreas and liver, where GCK activity regulates insulin secretion and glycogen synthesis, respectively. GCK’s low affinity for glucose and the sigmoidal substrate dependency of enzymatic turnover enables it to act as a sensor that makes cells responsive to changes in circulating glucose levels. Its unusual kinetic properties are intrinsically linked to the enzyme’s conformational dynamics. Accordingly, genetic variants that alter the dynamics or other aspects of GCK function are linked to three glucose homeostasis diseases. In this review, we describe the enzyme GCK, focusing on its role as a glucose sensor, its unusual kinetic properties, and recent large-scale efforts to assess GCK variant effects.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 3","pages":"Pages 255-266"},"PeriodicalIF":11.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
DNA can fold into noncanonical left-handed Z-DNA conformation beyond the right-handed B-DNA. While its crystal structure was discovered nearly four decades ago, it was predominantly considered a structural curiosity. Recent evidence suggests that Z-DNA formation occurs in nuclear and mitochondrial DNA (mtDNA), with significant biological implications. However, our understanding of its roles remains in its infancy, primarily due to a lack of study tools. In this review we summarize the structure and function of Z-DNA within the genome while addressing the difficulties associated with identifying and investigating its role(s). We then critically evaluate several intracellular factors that can modulate and regulate Z-DNA. Additionally, we discuss the recent technological and methodological advances that may overcome the challenges and enhance our understanding of Z-DNA.
{"title":"Z-DNA at the crossroads: untangling its role in genome dynamics","authors":"Vinodh J. Sahayasheela , Mitsuharu Ooga , Tomotaka Kumagai , Hiroshi Sugiyama","doi":"10.1016/j.tibs.2025.01.001","DOIUrl":"10.1016/j.tibs.2025.01.001","url":null,"abstract":"<div><div>DNA can fold into noncanonical left-handed Z-DNA conformation beyond the right-handed B-DNA. While its crystal structure was discovered nearly four decades ago, it was predominantly considered a structural curiosity. Recent evidence suggests that Z-DNA formation occurs in nuclear and mitochondrial DNA (mtDNA), with significant biological implications. However, our understanding of its roles remains in its infancy, primarily due to a lack of study tools. In this review we summarize the structure and function of Z-DNA within the genome while addressing the difficulties associated with identifying and investigating its role(s). We then critically evaluate several intracellular factors that can modulate and regulate Z-DNA. Additionally, we discuss the recent technological and methodological advances that may overcome the challenges and enhance our understanding of Z-DNA.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 3","pages":"Pages 267-279"},"PeriodicalIF":11.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/j.tibs.2024.12.013
Hongrui Liu , Meenakshi Pillai , Anthony K.L. Leung
Biomolecular condensates are cellular compartments that selectively enrich proteins and other macromolecules despite lacking enveloping membranes. These compartments often form through phase separation triggered by multivalent nucleic acids. Emerging data have revealed that poly(ADP-ribose) (PAR), a nucleic acid-based protein modification catalyzed by ADP-ribosyltransferases (commonly known as PARPs), plays a crucial role in this process. This review focuses on the role of PARPs and ADP-ribosylation, and explores the principles and mechanisms by which PAR regulates condensate formation, dissolution, and dynamics. Future studies with advanced tools to examine PAR binding sites, substrate interactions, PAR length and structure, and transitions from condensates to aggregates will be key to unraveling the complexity of ADP-ribosylation in health and disease, including cancer, viral infection, and neurodegeneration.
{"title":"PARPs and ADP-ribosylation-mediated biomolecular condensates: determinants, dynamics, and disease implications","authors":"Hongrui Liu , Meenakshi Pillai , Anthony K.L. Leung","doi":"10.1016/j.tibs.2024.12.013","DOIUrl":"10.1016/j.tibs.2024.12.013","url":null,"abstract":"<div><div>Biomolecular condensates are cellular compartments that selectively enrich proteins and other macromolecules despite lacking enveloping membranes. These compartments often form through phase separation triggered by multivalent nucleic acids. Emerging data have revealed that poly(ADP-ribose) (PAR), a nucleic acid-based protein modification catalyzed by ADP-ribosyltransferases (commonly known as PARPs), plays a crucial role in this process. This review focuses on the role of PARPs and ADP-ribosylation, and explores the principles and mechanisms by which PAR regulates condensate formation, dissolution, and dynamics. Future studies with advanced tools to examine PAR binding sites, substrate interactions, PAR length and structure, and transitions from condensates to aggregates will be key to unraveling the complexity of ADP-ribosylation in health and disease, including cancer, viral infection, and neurodegeneration.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 3","pages":"Pages 224-241"},"PeriodicalIF":11.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/S0968-0004(25)00035-0
{"title":"Advisory Board and Contents","authors":"","doi":"10.1016/S0968-0004(25)00035-0","DOIUrl":"10.1016/S0968-0004(25)00035-0","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 3","pages":"Pages i-ii"},"PeriodicalIF":11.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/j.tibs.2024.12.008
Nathaniel Hess , Jerelle A. Joseph
Biomolecular condensates are membraneless organelles that concentrate proteins and nucleic acids. One of the primary components of condensates is multidomain proteins, whose domains can be broadly classified as structured and disordered. While structured protein domains are ubiquitous within biomolecular condensates, the physical ramifications of their unique properties have been relatively underexplored. Therefore, this review synthesizes current literature pertaining to structured protein domains within the context of condensates. We examine how the propensity of structured domains for high interaction specificity and low conformational heterogeneity contributes to the formation, material properties, and functions of biomolecular condensates. Finally, we propose unanswered questions on the behavior of structured protein domains within condensates, the answers of which will contribute to a more complete understanding of condensate biophysics.
{"title":"Structured protein domains enter the spotlight: modulators of biomolecular condensate form and function","authors":"Nathaniel Hess , Jerelle A. Joseph","doi":"10.1016/j.tibs.2024.12.008","DOIUrl":"10.1016/j.tibs.2024.12.008","url":null,"abstract":"<div><div>Biomolecular condensates are membraneless organelles that concentrate proteins and nucleic acids. One of the primary components of condensates is multidomain proteins, whose domains can be broadly classified as structured and disordered. While structured protein domains are ubiquitous within biomolecular condensates, the physical ramifications of their unique properties have been relatively underexplored. Therefore, this review synthesizes current literature pertaining to structured protein domains within the context of condensates. We examine how the propensity of structured domains for high interaction specificity and low conformational heterogeneity contributes to the formation, material properties, and functions of biomolecular condensates. Finally, we propose unanswered questions on the behavior of structured protein domains within condensates, the answers of which will contribute to a more complete understanding of condensate biophysics.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 3","pages":"Pages 206-223"},"PeriodicalIF":11.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/S0968-0004(25)00038-6
{"title":"Subscription and Copyright Information","authors":"","doi":"10.1016/S0968-0004(25)00038-6","DOIUrl":"10.1016/S0968-0004(25)00038-6","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 3","pages":"Page e1"},"PeriodicalIF":11.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-25DOI: 10.1016/j.tibs.2025.01.009
Caitlin L Gare, Andrew M White, Lara R Malins
Peptides are a powerful drug modality with potential to access difficult targets. This recognition underlies their growth in the global pharmaceutical market, with peptides representing ~8% of drugs approved by the FDA over the past decade. Currently, the peptide therapeutic landscape is evolving, with high-throughput display technologies driving the identification of peptide leads with enhanced diversity. Yet, chemical modifications remain essential for improving the 'drug-like' properties of peptides and ultimately translating leads to market. In this review, we explore two recent therapeutic candidates (semaglutide, a peptide hormone analogue, and MK-0616, an mRNA display-derived candidate) as case studies that highlight general approaches to improving pharmacokinetics (PK) and potency. We also emphasize the critical link between advances in medicinal chemistry and the optimisation of highly efficacious peptide therapeutics.
{"title":"From lead to market: chemical approaches to transform peptides into therapeutics.","authors":"Caitlin L Gare, Andrew M White, Lara R Malins","doi":"10.1016/j.tibs.2025.01.009","DOIUrl":"https://doi.org/10.1016/j.tibs.2025.01.009","url":null,"abstract":"<p><p>Peptides are a powerful drug modality with potential to access difficult targets. This recognition underlies their growth in the global pharmaceutical market, with peptides representing ~8% of drugs approved by the FDA over the past decade. Currently, the peptide therapeutic landscape is evolving, with high-throughput display technologies driving the identification of peptide leads with enhanced diversity. Yet, chemical modifications remain essential for improving the 'drug-like' properties of peptides and ultimately translating leads to market. In this review, we explore two recent therapeutic candidates (semaglutide, a peptide hormone analogue, and MK-0616, an mRNA display-derived candidate) as case studies that highlight general approaches to improving pharmacokinetics (PK) and potency. We also emphasize the critical link between advances in medicinal chemistry and the optimisation of highly efficacious peptide therapeutics.</p>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advances in small RNA sequencing have revealed diverse small noncoding RNAs (sncRNAs) beyond microRNAs (miRNAs), derived from transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), and Y RNAs, carrying distinct RNA modifications. These emerging sncRNAs can function beyond RNA interference (RNAi), adopting aptamer-like roles by interacting with Toll-like receptors 7 and 8 (TLR7 and TLR8) via specific sequences, modifications, and structures. We propose a Sequential Activation Hypothesis where initial abnormal sncRNAs - triggered by infections or stresses - activate TLR7/8, leading to autoantibody production against autoantigens like RNA-binding proteins La and Ro. These autoantibody-antigen complexes further promote secondary immunogenic sncRNA production and repetitive TLR7/8 activation, perpetuating a vicious cycle sustaining autoimmunity. TLR7/8's X chromosome location and sex-biased expression contribute to female-dominant autoimmune diseases. Understanding sncRNA-TLR interactions is essential for designing novel therapeutic strategies.
{"title":"Small RNA and Toll-like receptor interactions: origins and disease mechanisms.","authors":"Jiancheng Yu, Xudong Zhang, Chen Cai, Tong Zhou, Qi Chen","doi":"10.1016/j.tibs.2025.01.004","DOIUrl":"10.1016/j.tibs.2025.01.004","url":null,"abstract":"<p><p>Advances in small RNA sequencing have revealed diverse small noncoding RNAs (sncRNAs) beyond microRNAs (miRNAs), derived from transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), and Y RNAs, carrying distinct RNA modifications. These emerging sncRNAs can function beyond RNA interference (RNAi), adopting aptamer-like roles by interacting with Toll-like receptors 7 and 8 (TLR7 and TLR8) via specific sequences, modifications, and structures. We propose a Sequential Activation Hypothesis where initial abnormal sncRNAs - triggered by infections or stresses - activate TLR7/8, leading to autoantibody production against autoantigens like RNA-binding proteins La and Ro. These autoantibody-antigen complexes further promote secondary immunogenic sncRNA production and repetitive TLR7/8 activation, perpetuating a vicious cycle sustaining autoimmunity. TLR7/8's X chromosome location and sex-biased expression contribute to female-dominant autoimmune diseases. Understanding sncRNA-TLR interactions is essential for designing novel therapeutic strategies.</p>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tibs.2024.12.003
Anitha Rajendran , Carlos A. Castañeda
Protein quality control (PQC) mechanisms including the ubiquitin (Ub)-proteasome system (UPS), autophagy, and chaperone-mediated refolding are essential to maintain protein homeostasis in cells. Recent studies show that these PQC mechanisms are further modulated by biomolecular condensates that sequester PQC components and compartmentalize reactions. Accumulating evidence points towards the PQC machinery playing a pivotal role in regulating the assembly, disassembly, and viscoelastic properties of several condensates. Here, we discuss how the PQC machinery can form their own condensates and also be recruited to known condensates under physiological or stress-induced conditions. We present molecular insights into how the multivalent architecture of polyUb chains, Ub-binding adaptor proteins, and other PQC machinery contribute to condensate assembly, leading to the regulation of downstream PQC outcomes and therapeutic potential.
{"title":"Protein quality control machinery: regulators of condensate architecture and functionality","authors":"Anitha Rajendran , Carlos A. Castañeda","doi":"10.1016/j.tibs.2024.12.003","DOIUrl":"10.1016/j.tibs.2024.12.003","url":null,"abstract":"<div><div>Protein quality control (PQC) mechanisms including the ubiquitin (Ub)-proteasome system (UPS), autophagy, and chaperone-mediated refolding are essential to maintain protein homeostasis in cells. Recent studies show that these PQC mechanisms are further modulated by biomolecular condensates that sequester PQC components and compartmentalize reactions. Accumulating evidence points towards the PQC machinery playing a pivotal role in regulating the assembly, disassembly, and viscoelastic properties of several condensates. Here, we discuss how the PQC machinery can form their own condensates and also be recruited to known condensates under physiological or stress-induced conditions. We present molecular insights into how the multivalent architecture of polyUb chains, Ub-binding adaptor proteins, and other PQC machinery contribute to condensate assembly, leading to the regulation of downstream PQC outcomes and therapeutic potential.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 106-120"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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