Nature Structural & Molecular Biology最新文献

{"title":"Designing non-natural RNA-guided nucleases","authors":"Aparna Anantharaman","doi":"10.1038/s41594-026-01867-8","DOIUrl":"10.1038/s41594-026-01867-8","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 8","pages":"1127-1128"},"PeriodicalIF":10.1,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148710539","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}

{"title":"Structural and molecular principles of DAMP biology","authors":"Ruochan Chen, Ju Zou, Jie Li, Jiawang Chen, Xiao Zhong, Jiao Liu, Rui Kang, Huiting Zhou, Daolin Tang","doi":"10.1038/s41594-026-01858-9","DOIUrl":"10.1038/s41594-026-01858-9","url":null,"abstract":"Damage-associated molecular patterns (DAMPs) are endogenous danger signals. They can be preformed molecules released upon membrane rupture and stress-induced or newly generated factors arising during cell death. These signals link cellular demise to diverse host responses. Rather than passive by-products, DAMPs are actively mobilized through membrane-remodeling proteins, vesicular trafficking and metabolic regulation. Conformational changes, oligomerization and post-translational modifications shape their release and immunogenicity, as illustrated by redox-dependent DAMP states, pore-forming gasdermins and MLKL, and NINJ1-mediated membrane rupture. At the sensing interface, receptors such as TLR4, P2X7 and AGER, together with cytosolic STING1 pathways, translate DAMP recognition into downstream signaling through assembly-driven mechanisms. Cross-talk with metabolic pathways and membrane repair systems, including ESCRT-III and autophagy, further refines DAMP signaling dynamics. Here, we survey and contextualize recent literature to provide a structural and molecular framework for understanding how DAMPs encode immune outcomes and highlight opportunities for targeted therapeutic intervention. In this Review, the authors outline mechanisms through which damage-associated molecular patterns encode immune outcomes.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 8","pages":"1131-1146"},"PeriodicalIF":10.1,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148710541","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}

{"title":"Greg Hannon (1964–2026)","authors":"Emily Bernstein, Michelle Carmell","doi":"10.1038/s41594-026-01862-z","DOIUrl":"10.1038/s41594-026-01862-z","url":null,"abstract":"Greg Hannon was an inspirational mentor who shaped modern RNA biology.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 8","pages":"1117-1118"},"PeriodicalIF":10.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-026-01862-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148710540","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}

{"title":"Alzheimer’s disease-linked Flemish APP mutation defines a distinct amyloid-β fold","authors":"","doi":"10.1038/s41594-026-01854-z","DOIUrl":"10.1038/s41594-026-01854-z","url":null,"abstract":"Cryogenic electron microscopy shows that the rare Flemish mutation in the amyloid-β precursor protein drives Aβ40 (an amyloid-β peptide) to assemble into a distinct filament fold. By exposing a phenylalanine residue, this fold creates a molecular feature that might explain the vascular accumulation of Aβ40 and associated cerebral hemorrhage in individuals carrying the Flemish mutation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 8","pages":"1129-1130"},"PeriodicalIF":10.1,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148685166","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}

{"title":"Distinct amyloid-β filament fold in individuals with APP Flemish mutation","authors":"Peerzada Shariq Shaheen Khaki, Pablo Adrian Guillen-Poza, Carlton Wong, Chloe Kan, Rakesh Sharma, Rio Sugimura, Andrew C. Robinson, Alejandro Valbuena, Roy Chun-Laam NG, Yang Yang, Ruben Hervas","doi":"10.1038/s41594-026-01855-y","DOIUrl":"10.1038/s41594-026-01855-y","url":null,"abstract":"The dominantly inherited Flemish mutation—an A692G substitution in the amyloid precursor protein, corresponding to an A21G change in amyloid-β (Aβ)—causes a rare, early-onset form of Alzheimer disease characterized by pronounced cerebral amyloid angiopathy and unusually large senile plaque cores. Here, we report cryo-electron microscopy structures of amyloid filaments extracted from the postmortem parietal lobes of two individuals representing the only two known Flemish pedigrees worldwide. Although tau paired helical filaments were present, the predominant filaments comprise Aβ40-A21G, assembled as two identical protofilaments (D1–V40) packed with two-start helical symmetry. Aβ40-A21G and wild-type Aβ42 filaments share a substructure preceding the substitution site (Y10–F19); however, loss of the methyl group at residue 21 gives rise to a distinct arrangement, termed the ‘Flemish fold’, which differs from all previously characterized Aβ folds and is defined by a unique hydrophobic interface. Using a cell-based assay, we find that this distinctive fold is associated with the vascular tropism characteristic of the Flemish variant. Together, our structural and cellular data define a familial Alzheimer-disease-associated amyloid fold and provide insight into the molecular basis of Flemish-type dementia and cerebral hemorrhage. Brain samples from individuals with the rare APP Flemish mutation reveal a distinct amyloid-β filament fold that may help explain the accumulation of amyloid-β in blood vessels in inherited Alzheimer disease.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 8","pages":"1194-1203"},"PeriodicalIF":10.1,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148685184","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}

{"title":"Factors modulating the assembly of human β2-adrenergic receptor–β-arrestin complexes","authors":"Florian M. Wilhelm, Kristyna Pluhackova, John Janetzko, Matthieu Masureel, Erin Marsh, Jesse Hudspeth, Wenzel Gaßner, Gebhard F. X. Schertler, Brian K. Kobilka, Daniel J. Müller","doi":"10.1038/s41594-026-01842-3","DOIUrl":"10.1038/s41594-026-01842-3","url":null,"abstract":"β-arrestins, pivotal regulators of G protein-coupled receptor (GPCR) signaling, assemble with hundreds of GPCRs. How this assembly rises to functionally distinct complexes in which β-arrestin engages the GPCR tail, core or both, remains a central question. Here employing single-molecule force spectroscopy and molecular dynamics simulations, we monitor assembly of β2-adrenergic receptor (β2AR)–β-arrestin2 (βarr2) tail, core and tail–core complexes in phospholipid membranes and dissect their mechanical and kinetic stabilities. We show that βarr2 engages the phosphorylated β2AR carboxy-terminus (C-tail) within milliseconds, much faster than the active receptor core. In addition, the phospholipid membrane contributes substantially to complex stability, with phosphatidylinositol 4,5-bisphosphate (PIP2) modulating stability and conformation. While PIP2 stabilizes the β2AR–βarr2 core, it precludes βarr2 from concomitantly binding the phosphorylated β2AR C-tail. βarr2 activation and PIP2 strengthen βarr2–membrane association through insertion of the C-edge and finger loop. These findings establish PIP2, alongside ligand binding and receptor phosphorylation, as a central determinant of β2AR–βarr2 complex assembly, offering mechanistic insight into the regulation of GPCR signaling. Wilhelm, Pluhackova and colleagues show how ligand binding, receptor phosphorylation and membrane interactions, including PIP2, drive the assembly of human β2-adrenergic receptor–β-arrestin complexes, providing insight into structural mechanisms regulating GPCR signaling.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 8","pages":"1158-1170"},"PeriodicalIF":10.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-026-01842-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648928","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}

{"title":"A coupled TOM–TIM22 supercomplex in human mitochondrial protein import","authors":"Doron Rapaport, Johannes M. Herrmann","doi":"10.1038/s41594-026-01852-1","DOIUrl":"10.1038/s41594-026-01852-1","url":null,"abstract":"TOM and TIM22 complexes facilitate the transport of carrier protein substrates into mitochondria. New work shows that, in human mitochondria, these two protein complexes form transient supercomplexes to facilitate protein biogenesis.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 8","pages":"1125-1126"},"PeriodicalIF":10.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648888","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}

{"title":"Variant characterization in the intrinsically disordered human proteome","authors":"Dalmira Hubrich, Jesus Alvarado Valverde, Chop Yan Lee, Milena Djokic, Mareen Welzel, Kristina Hintz, Joelle Morgan Strom, Katja Luck","doi":"10.1038/s41594-026-01846-z","DOIUrl":"10.1038/s41594-026-01846-z","url":null,"abstract":"Variant effect prediction remains a key challenge in precision medicine. Computational models are increasingly successful in the characterization of missense variants in folded protein regions. However, 37% of all annotated missense variants reside in the 25% of the proteome that is intrinsically disordered, lacking positional sequence conservation and stable structures. To advance the characterization of variants in intrinsically disordered protein regions (IDRs), we combined sequence pattern searches with AlphaFold to structurally annotate 1,300 protein–protein interactions with interfaces mediated by short disordered motifs binding to folded domains in partner proteins. These interfaces were selected based on their overlap with uncertain missense variants enabling structural model-based prediction of deleterious effects of 1,187 of these variants in IDRs. Extensive experimental efforts validated the predicted interfaces and deleterious variant effects that were predicted as benign by AlphaMissense, demonstrating that the combination of sequence analysis and structural modeling can readily generate numerous testable hypotheses of variant effects on protein function in IDRs. Proteome-wide prediction and structural modeling of disordered protein interaction interfaces advance characterization of disease-associated variants in disordered protein regions.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 8","pages":"1183-1193"},"PeriodicalIF":10.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648912","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}

{"title":"Protein thiol alterations drive pathologic liquid–liquid phase separation in the aging brain","authors":"Thibaut Vignane, Martín Hugo, Christian Hoffmann, Polina Reichert, Antonia Katsouda, Davide D’Andrea, Han Wang, Johannes V. Tromm, Marko Miler, Ferran Comas, Dunja Petrovic, Suyuan Chen, Jan Lj. Miljkovic, Danail Stoychev, Erik Lacko, Vladimir M. Jovanovic, Suwarna Chakraborty, Sunil J. Tripathi, Edwin Vázquez-Rosa, Jordan L. Morris, Suvagata Roy Chowdhury, Julien Prudent, Albert Sickmann, Natalija Polovic, Andrew A. Pieper, Ilan Davis, Kostas Tokatlidis, Bindu D. Paul, Michael P. Murphy, Christian Münch, Andreas Papapetropoulos, Dragomir Milovanovic, Milos R. Filipovic","doi":"10.1038/s41594-026-01857-w","DOIUrl":"10.1038/s41594-026-01857-w","url":null,"abstract":"Cellular homeostasis relies on regulation of processes, including protein post-translational modifications (PTMs) and biomolecular condensation. Aging disrupts the equilibrium of these processes, increasing susceptibility to disease and mortality. Here we used chemoproteomic techniques to generate an atlas of cysteine PTMs in the mouse brain and showed that age-related increases in thiol oxidation promoted the formation of biomolecular condensates. By contrast, protein persulfidation, regulated by hydrogen sulfide production, inhibited biomolecular condensation, preserving protein function. Age-induced alterations in cysteine PTMs influenced the phase separation properties of synapsin 1 and G3BP2, leading to impaired neurotransmitter release and defective stress granule formation and resolution, features associated with aging and neurodegenerative diseases. Mice deficient in cystathionine γ-lyase, the enzyme responsible for hydrogen sulfide production, exhibited reduced lifespans and spontaneously developed protein aggregates with age. Our results highlight the therapeutic potential of protein persulfidation in reversal of dysregulated biomolecular condensation and suggest that sulfide donors could be used to mitigate age-related diseases. Vignane et al. show that age-related protein oxidation disrupts normal brain protein organization, promoting harmful condensates and aggregation linked to neurodegeneration, whereas hydrogen sulfide-driven persulfidation counteracts these effects.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 8","pages":"1252-1265"},"PeriodicalIF":10.1,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-026-01857-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148612618","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}

{"title":"A protective ESCRT sleeve for ultrafine DNA bridges","authors":"Yves Barral, Manuel Mendoza","doi":"10.1038/s41594-026-01856-x","DOIUrl":"10.1038/s41594-026-01856-x","url":null,"abstract":"DNA bridges, thin DNA connections that link daughter cells after division, threaten genome integrity and can trigger catastrophic chromosome rearrangements. A new study proposes that ESCRT-III proteins form protective assemblies around fragile ultrafine DNA bridges, revealing an unexpected role for these membrane-remodeling complexes in genome protection.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 8","pages":"1122-1124"},"PeriodicalIF":10.1,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620698","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}