Pub Date : 2025-12-09DOI: 10.1016/j.tibs.2025.11.003
Mohd Y Bhat, Xin Liu
Polycomb repressive complex 2 (PRC2) is a key epigenetic enzyme complex that mediates developmental gene repression mainly by depositing the repressive H3K27me3 histone mark. PRC2 operates through its distinct forms, PRC2.1 and PRC2.2, each defined by unique accessory subunits, with additional complexity introduced by other molecular variants such as developmentally regulated homologs and isoforms. PRC2 function is primarily dictated by its enzymatic activity and chromatin recruitment, both of which are rigorously controlled during development and can be dysregulated by disease-associated mutations and oncoproteins. Structural biology has begun to provide important mechanistic insights into various aspects of PRC2 assembly, catalysis, chromatin targeting, and cellular regulation at atomic resolution, addressing several longstanding questions about the Polycomb repression system.
{"title":"Emerging structural insights into PRC2 function in development and disease.","authors":"Mohd Y Bhat, Xin Liu","doi":"10.1016/j.tibs.2025.11.003","DOIUrl":"https://doi.org/10.1016/j.tibs.2025.11.003","url":null,"abstract":"<p><p>Polycomb repressive complex 2 (PRC2) is a key epigenetic enzyme complex that mediates developmental gene repression mainly by depositing the repressive H3K27me3 histone mark. PRC2 operates through its distinct forms, PRC2.1 and PRC2.2, each defined by unique accessory subunits, with additional complexity introduced by other molecular variants such as developmentally regulated homologs and isoforms. PRC2 function is primarily dictated by its enzymatic activity and chromatin recruitment, both of which are rigorously controlled during development and can be dysregulated by disease-associated mutations and oncoproteins. Structural biology has begun to provide important mechanistic insights into various aspects of PRC2 assembly, catalysis, chromatin targeting, and cellular regulation at atomic resolution, addressing several longstanding questions about the Polycomb repression system.</p>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":" ","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720004","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 : 2025-12-05DOI: 10.1016/j.tibs.2025.11.002
Denis Lacabanne, Jonathan J Ruprecht, Maximilian Sichrovsky, Lucy R Forrest, Vanessa Leone, Sotiria Tavoulari, Edmund R S Kunji
The mitochondrial pyruvate carrier (MPC), of the SLC54 family of solute carriers, has a critical role in eukaryotic energy metabolism by transporting pyruvate, the end-product of glycolysis, into the mitochondrial matrix. Recently, structures of the human MPC1/MPC2 and MPC1L/MPC2 heterodimers in the outward-open, occluded, and inward-open states have been determined by cryo-electron microscopy (cryo-EM) and by AlphaFold modeling. In this review we discuss the membrane orientation, substrate binding site properties, and structural features of the alternating access mechanism of the carrier, as well as the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state. These structural studies will support drug development efforts for the treatment of diabetes mellitus, neurodegeneration, metabolic dysfunction-associated steatotic liver disease (MASLD), and some types of cancers.
{"title":"Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.","authors":"Denis Lacabanne, Jonathan J Ruprecht, Maximilian Sichrovsky, Lucy R Forrest, Vanessa Leone, Sotiria Tavoulari, Edmund R S Kunji","doi":"10.1016/j.tibs.2025.11.002","DOIUrl":"https://doi.org/10.1016/j.tibs.2025.11.002","url":null,"abstract":"<p><p>The mitochondrial pyruvate carrier (MPC), of the SLC54 family of solute carriers, has a critical role in eukaryotic energy metabolism by transporting pyruvate, the end-product of glycolysis, into the mitochondrial matrix. Recently, structures of the human MPC1/MPC2 and MPC1L/MPC2 heterodimers in the outward-open, occluded, and inward-open states have been determined by cryo-electron microscopy (cryo-EM) and by AlphaFold modeling. In this review we discuss the membrane orientation, substrate binding site properties, and structural features of the alternating access mechanism of the carrier, as well as the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state. These structural studies will support drug development efforts for the treatment of diabetes mellitus, neurodegeneration, metabolic dysfunction-associated steatotic liver disease (MASLD), and some types of cancers.</p>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":" ","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695679","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 : 2025-12-01DOI: 10.1016/S0968-0004(25)00284-1
{"title":"Subscription and Copyright Information","authors":"","doi":"10.1016/S0968-0004(25)00284-1","DOIUrl":"10.1016/S0968-0004(25)00284-1","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 12","pages":"Page e1"},"PeriodicalIF":11.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665543","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 : 2025-12-01DOI: 10.1016/j.tibs.2025.07.008
Jorge El-Azaz , Hiroshi A. Maeda
The shikimate and aromatic amino acid (AAA) biosynthetic pathways are crucial for the production of L-phenylalanine (Phe), L-tyrosine (Tyr), and L-tryptophan (Trp), as well as vitamins, hormones, and an array of plant natural products, including lignin, a major reservoir of organic carbon on Earth. In this review, we summarize recent advances in the mechanisms that dynamically regulate the AAA biosynthetic pathways of plants, with a particular focus on Phe biosynthesis due to its central role as a precursor to phenylpropanoids. The integration of AAA biosynthesis with upstream and downstream plant metabolism is also discussed, as well as how this fundamental knowledge can inform the bioengineering of plant-based platforms for sustainable production of AAA-derived natural products.
{"title":"The multilayered regulation of aromatic amino acid biosynthesis in plants","authors":"Jorge El-Azaz , Hiroshi A. Maeda","doi":"10.1016/j.tibs.2025.07.008","DOIUrl":"10.1016/j.tibs.2025.07.008","url":null,"abstract":"<div><div>The shikimate and aromatic amino acid (AAA) biosynthetic pathways are crucial for the production of L-phenylalanine (Phe), L-tyrosine (Tyr), and L-tryptophan (Trp), as well as vitamins, hormones, and an array of plant natural products, including lignin, a major reservoir of organic carbon on Earth. In this review, we summarize recent advances in the mechanisms that dynamically regulate the AAA biosynthetic pathways of plants, with a particular focus on Phe biosynthesis due to its central role as a precursor to phenylpropanoids. The integration of AAA biosynthesis with upstream and downstream plant metabolism is also discussed, as well as how this fundamental knowledge can inform the bioengineering of plant-based platforms for sustainable production of AAA-derived natural products.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 12","pages":"Pages 1051-1071"},"PeriodicalIF":11.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938185","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 : 2025-12-01DOI: 10.1016/j.tibs.2025.09.003
Ralph H. Kehlenbach , Yuh Min Chook
CRM1 (Exportin 1, XPO1), the best-characterized nuclear export receptor, exports hundreds of proteins and various RNA species. Its broad cargo repertoire necessitates versatile binding modes for diverse interaction partners, including nuclear export signal/sequence (NES)-containing cargoes, the GTPase Ran, nucleoporins that line nuclear pore complexes, and accessory proteins that facilitate export complex assembly or disassembly. We review the current knowledge of CRM1’s protein and RNA cargoes and examine its modes of interactions in the context of the basic mechanism of nuclear export – NES recognition, recent structural studies that reveal how CRM1 engages cargoes beyond NESs, and allosteric regulation. Finally, we touch on the state of NES/cargo prediction, CRM1’s interactions with nucleoporins, and its emerging roles beyond nuclear export.
{"title":"The nuclear export receptor CRM1/XPO1 and its diverse cargoes","authors":"Ralph H. Kehlenbach , Yuh Min Chook","doi":"10.1016/j.tibs.2025.09.003","DOIUrl":"10.1016/j.tibs.2025.09.003","url":null,"abstract":"<div><div>CRM1 (Exportin 1, XPO1), the best-characterized nuclear export receptor, exports hundreds of proteins and various RNA species. Its broad cargo repertoire necessitates versatile binding modes for diverse interaction partners, including nuclear export signal/sequence (NES)-containing cargoes, the GTPase Ran, nucleoporins that line nuclear pore complexes, and accessory proteins that facilitate export complex assembly or disassembly. We review the current knowledge of CRM1’s protein and RNA cargoes and examine its modes of interactions in the context of the basic mechanism of nuclear export – NES recognition, recent structural studies that reveal how CRM1 engages cargoes beyond NESs, and allosteric regulation. Finally, we touch on the state of NES/cargo prediction, CRM1’s interactions with nucleoporins, and its emerging roles beyond nuclear export.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 12","pages":"Pages 1131-1144"},"PeriodicalIF":11.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184493","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 : 2025-12-01DOI: 10.1016/j.tibs.2025.09.004
Abi S. Ghifari , Carmela Vazquez-Calvo , Andreas Carlström , Martin Ott
Mitochondrial protein homeostasis (proteostasis) keeps the mitochondrial proteome functional. Thus, proteostasis is essential for mitochondrial activity and overall cellular functions, and a reduction in its function corresponds with diseases and aging in humans. Recent studies in various model organisms highlight components and mechanisms of mitochondrial proteostasis from biogenesis, through assembly, to turnover. Key findings include the identification of new components and mechanistic insights into protein import and mitochondrial translation processes, the interconnectivity of protein biogenesis and quality control, and proteolytic degradation machineries. In this review we discuss these advances that improve our current understanding of the inner workings and significance of the mitochondrial proteostasis network in maintaining functional mitochondria.
{"title":"Interconnectivity of mitochondrial protein biogenesis and quality control","authors":"Abi S. Ghifari , Carmela Vazquez-Calvo , Andreas Carlström , Martin Ott","doi":"10.1016/j.tibs.2025.09.004","DOIUrl":"10.1016/j.tibs.2025.09.004","url":null,"abstract":"<div><div>Mitochondrial protein homeostasis (proteostasis) keeps the mitochondrial proteome functional. Thus, proteostasis is essential for mitochondrial activity and overall cellular functions, and a reduction in its function corresponds with diseases and aging in humans. Recent studies in various model organisms highlight components and mechanisms of mitochondrial proteostasis from biogenesis, through assembly, to turnover. Key findings include the identification of new components and mechanistic insights into protein import and mitochondrial translation processes, the interconnectivity of protein biogenesis and quality control, and proteolytic degradation machineries. In this review we discuss these advances that improve our current understanding of the inner workings and significance of the mitochondrial proteostasis network in maintaining functional mitochondria.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 12","pages":"Pages 1102-1117"},"PeriodicalIF":11.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224665","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 : 2025-12-01DOI: 10.1016/j.tibs.2025.10.002
Dongxue Wang (王冬雪) , Jing Yang (杨靖)
A recent study by Ding et al. harnesses cutting-edge proteomics to explore protein changes linked to human aging over 50 years across 12 tissues and plasma. It uncovered asynchronous aging clocks in different organs, redefining aging as a coordinated, targetable network.
{"title":"Unlocking the protein code: how our organs age across a lifetime","authors":"Dongxue Wang (王冬雪) , Jing Yang (杨靖)","doi":"10.1016/j.tibs.2025.10.002","DOIUrl":"10.1016/j.tibs.2025.10.002","url":null,"abstract":"<div><div>A recent study by <span><span>Ding <em>et al.</em></span><svg><path></path></svg></span> harnesses cutting-edge proteomics to explore protein changes linked to human aging over 50 years across 12 tissues and plasma. It uncovered asynchronous aging clocks in different organs, redefining aging as a coordinated, targetable network.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 12","pages":"Pages 1049-1050"},"PeriodicalIF":11.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145547578","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 : 2025-12-01DOI: 10.1016/j.tibs.2025.08.004
Michaela Oborská-Oplová , Michael A. Ruoss , Vikram G. Panse
Cells depend on the efficient import of thousands of nuclear-encoded mitochondrial proteins to maintain mitochondrial function. A new study by Flohr et al. reveals a quality control strategy that traps a subset of mitochondrial precursors in the intermembrane space during energy stress, preventing their toxic accumulation in the cytosol or nucleus.
{"title":"MitoTraP: mitochondrial protection for cellular proteostasis","authors":"Michaela Oborská-Oplová , Michael A. Ruoss , Vikram G. Panse","doi":"10.1016/j.tibs.2025.08.004","DOIUrl":"10.1016/j.tibs.2025.08.004","url":null,"abstract":"<div><div>Cells depend on the efficient import of thousands of nuclear-encoded mitochondrial proteins to maintain mitochondrial function. A new study by <span><span>Flohr <em>et al</em></span><svg><path></path></svg></span><em>.</em> reveals a quality control strategy that traps a subset of mitochondrial precursors in the intermembrane space during energy stress, preventing their toxic accumulation in the cytosol or nucleus.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 12","pages":"Pages 1047-1048"},"PeriodicalIF":11.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938166","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 : 2025-12-01DOI: 10.1016/j.tibs.2025.09.006
Aixia Song , Danyi Lu , Fei Xavier Chen
Well-regulated transcription is essential for maintaining cellular homeostasis and genome integrity. The Integrator–PP2A complex has emerged as a major regulator of transcription by stimulating promoter-proximal termination of RNA polymerase II (Pol II). By employing dual catalytic activities, Integrator–PP2A shapes transcriptional output, limits aberrant RNA production, and suppresses R-loop–associated genome instability. Integrator–PP2A is highly modular, enabling dynamic interactions with transcription factors and epigenetic modifiers in distinct chromatin contexts and serving as a molecular hub that links transcriptional regulation to RNA quality control, chromatin state, and genome surveillance. Here, we review recent insights into the composition, mechanisms, and regulatory functions of this complex, which together establish its broad roles across both coding and noncoding transcriptional programs.
{"title":"The Integrator–PP2A complex integrates promoter-proximal premature termination with chromatin context and genome maintenance","authors":"Aixia Song , Danyi Lu , Fei Xavier Chen","doi":"10.1016/j.tibs.2025.09.006","DOIUrl":"10.1016/j.tibs.2025.09.006","url":null,"abstract":"<div><div>Well-regulated transcription is essential for maintaining cellular homeostasis and genome integrity. The Integrator–PP2A complex has emerged as a major regulator of transcription by stimulating promoter-proximal termination of RNA polymerase II (Pol II). By employing dual catalytic activities, Integrator–PP2A shapes transcriptional output, limits aberrant RNA production, and suppresses R-loop–associated genome instability. Integrator–PP2A is highly modular, enabling dynamic interactions with transcription factors and epigenetic modifiers in distinct chromatin contexts and serving as a molecular hub that links transcriptional regulation to RNA quality control, chromatin state, and genome surveillance. Here, we review recent insights into the composition, mechanisms, and regulatory functions of this complex, which together establish its broad roles across both coding and noncoding transcriptional programs.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 12","pages":"Pages 1118-1130"},"PeriodicalIF":11.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273483","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 : 2025-12-01DOI: 10.1016/j.tibs.2025.08.006
Sol C. Begue , Emanuela Leonardi , Silvio C.E. Tosatto
The rise of AlphaFold and similar structure predictors has made it possible to determine the 3D structure of almost any protein from its amino acid sequence. Residue interaction networks (RINs), graphs where residues are represented as nodes and interactions as edges, provide a powerful framework for analyzing and interpreting this surge in structural data. Here, we provide a comprehensive introduction to RINs, exploring different approaches to constructing and analyzing them, including their integration with molecular dynamics (MD) simulations and artificial intelligence (AI). To illustrate their versatility, we present different case studies where RINs have been applied to investigate thermostability, allosterism, post-translational modifications (PTMs), homology, and evolution. Finally, we discuss future directions for RINs, emphasizing opportunities for refinement and broader integration into structural biology.
{"title":"Decoding protein structures with residue interaction networks","authors":"Sol C. Begue , Emanuela Leonardi , Silvio C.E. Tosatto","doi":"10.1016/j.tibs.2025.08.006","DOIUrl":"10.1016/j.tibs.2025.08.006","url":null,"abstract":"<div><div>The rise of AlphaFold and similar structure predictors has made it possible to determine the 3D structure of almost any protein from its amino acid sequence. Residue interaction networks (RINs), graphs where residues are represented as nodes and interactions as edges, provide a powerful framework for analyzing and interpreting this surge in structural data. Here, we provide a comprehensive introduction to RINs, exploring different approaches to constructing and analyzing them, including their integration with molecular dynamics (MD) simulations and artificial intelligence (AI). To illustrate their versatility, we present different case studies where RINs have been applied to investigate thermostability, allosterism, post-translational modifications (PTMs), homology, and evolution. Finally, we discuss future directions for RINs, emphasizing opportunities for refinement and broader integration into structural biology.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 12","pages":"Pages 1072-1085"},"PeriodicalIF":11.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008056","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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