Molecular Cell最新文献_第6页

Simplifying in silico protein evolution with minimal screening by unZipro 简化硅蛋白进化与最小筛选的unZipro

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-24 DOI: 10.1016/j.molcel.2026.08.028

Zhaohui Qin,Sanzeng Zhao,Zhaolong Deng,Xiaomin Si,Cheng Xing,Zhenfei Zhang,Yumeng Zhang,Xueying Han,Jindong Zhang,Yang Chen,Xiaoyi Liu,Jinhui Li,Lei Fu,Liyuan You,James W. Murray,Huiyun Liu,Huifang Li,Chengwei Li,Song Wu,Junzhou Li,Zhen Chen,Jiangning Song,Daowen Wang,Xiang Ji

{"title":"Simplifying in silico protein evolution with minimal screening by unZipro","authors":"Zhaohui Qin,Sanzeng Zhao,Zhaolong Deng,Xiaomin Si,Cheng Xing,Zhenfei Zhang,Yumeng Zhang,Xueying Han,Jindong Zhang,Yang Chen,Xiaoyi Liu,Jinhui Li,Lei Fu,Liyuan You,James W. Murray,Huiyun Liu,Huifang Li,Chengwei Li,Song Wu,Junzhou Li,Zhen Chen,Jiangning Song,Daowen Wang,Xiang Ji","doi":"10.1016/j.molcel.2026.08.028","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.028","url":null,"abstract":"Despite the significant progress made in recent years, current AI-driven protein engineering methods often suffer from iterative experimental validation, limited success rates, modest improvements, and/or high computational costs. Moreover, their utility for evolving plant proteins remains unexplored. Here we present unZipro, an efficient, scalable, and generalizable framework for zero-shot, in silico protein evolution. unZipro integrates a compact, pre-trained inverse folding model with meta-learning to derive family-specific fitness landscapes. We demonstrate unZipro’s ability to directly identify high-activity variants from minimal libraries (∼10 candidates) with an average success rate of 61% across nine diverse proteins, achieving up to a 28-fold increase in the gene-editing activity of T5E-CasΦ2 fusion variants. Leveraging unZipro, we developed state-of-the-art plant gene-editing nucleases, superior firefly luciferase variants, enhanced rice transcription factors, and barley-derived antiviral proteins with elevated potency. Overall, unZipro represents a new paradigm for cost-effective, widely accessible, and transformative protein engineering in biology, biotechnology, and agriculture.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"162 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149027568","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}

引用次数: 0

CaMKII monomers are sufficient for GluN2B binding, co-condensation, and synaptic potentiation CaMKII单体足以结合GluN2B、共缩合和突触增强

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-23 DOI: 10.1016/j.molcel.2026.08.029

Carolyn Nicole Brown,C. Madison Barker,Carley N. Miller,Fan-Yi Chao,Jason Aoto,Steven J. Coultrap,K. Ulrich Bayer

{"title":"CaMKII monomers are sufficient for GluN2B binding, co-condensation, and synaptic potentiation","authors":"Carolyn Nicole Brown,C. Madison Barker,Carley N. Miller,Fan-Yi Chao,Jason Aoto,Steven J. Coultrap,K. Ulrich Bayer","doi":"10.1016/j.molcel.2026.08.029","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.029","url":null,"abstract":"Cognitive functions require synaptic plasticity, specifically long-term potentiation (LTP). LTP is thought to require Ca2+/CaM-dependent protein kinase II (CaMKII) binding to the NMDA-type glutamate receptor subunit GluN2B, but this poses a conundrum: truncated CaMKII monomers (without the hub domain that forms 12meric holoenzymes) fail to bind GluN2B within cells but still potentiate synapses when made constitutively active. We hypothesized that CaMKII monomer binding to GluN2B has just eluded detection. Instead, even though full-length CaMKII monomers (with hub-domain mutations) were found to indeed bind and even form condensates with GluN2B, truncated monomers were not. Nonetheless, truncated monomers still potentiated synapses, even in neurons with GluN2B mutations that ablate CaMKII binding. However, potentiation occurred only with monomers that were made Ca2+-independent by artificial phosphatase-resistant thio-autophosphorylation, not by regular autophosphorylation of T286. These findings support that CaMKII binding to GluN2B is required during physiological LTP induction because it generates the phosphatase-resistant autonomous activity that mediates LTP expression.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"7 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149019753","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}

引用次数: 0

Linker histone H1.0 loads onto nucleosomes through multiple pathways that are facilitated by histone chaperones 连接体组蛋白H1.0通过多种途径加载到核小体上，这些途径由组蛋白伴侣促进

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-22 DOI: 10.1016/j.molcel.2026.09.001

Ehsan Akbari,Nathaniel L. Burge,Matti Valdimarsson,Aritra Chowdhury,Benjamin Schuler,Michael G. Poirier

{"title":"Linker histone H1.0 loads onto nucleosomes through multiple pathways that are facilitated by histone chaperones","authors":"Ehsan Akbari,Nathaniel L. Burge,Matti Valdimarsson,Aritra Chowdhury,Benjamin Schuler,Michael G. Poirier","doi":"10.1016/j.molcel.2026.09.001","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.001","url":null,"abstract":"Linker histone H1 is an essential chromatin architectural protein that compacts chromatin into transcriptionally silent regions by interacting with nucleosomal and linker DNA while rapidly exchanging in vivo. How H1 targets nucleosomes while being dynamic remains unanswered. Using a single-molecule strategy, we investigated human H1.0 interactions with DNA and nucleosomes. H1.0 directly binds nucleosomes and naked DNA with a preference toward nucleosomes. DNA-bound H1.0 exhibited a range of bound lifetimes with both mobile and immobile states, where H1.0 was largely mobile, diffused over kilobase distances in seconds, but surprisingly did not load onto nucleosomes. Linker histone chaperones significantly facilitated H1.0-nucleosome loading by enabling H1.0 loading through DNA sliding, reducing DNA resident times without impacting nucleosome resident times, increasing mobility along DNA, and targeting H1.0 loading onto the nucleosome dyad. These findings reveal the multiple distinct mechanisms linker histones and their chaperones use to interact with nucleosomes to regulate chromatin accessibility.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"18 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149013590","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}

引用次数: 0

De novo-engineered guide RNA-directed transposition with TnpB-family proteins 用tnpb家族蛋白重新设计引导rna定向转位

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-17 DOI: 10.1016/j.molcel.2026.08.023

Richard D. Schargel,Laura Chacon Machado,Shravanika Kumaran,Jordan E. Thesier,Shreya S. Krishnan,Alba Guarné,Joseph E. Peters

{"title":"De novo-engineered guide RNA-directed transposition with TnpB-family proteins","authors":"Richard D. Schargel,Laura Chacon Machado,Shravanika Kumaran,Jordan E. Thesier,Shreya S. Krishnan,Alba Guarné,Joseph E. Peters","doi":"10.1016/j.molcel.2026.08.023","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.023","url":null,"abstract":"Programmable DNA integration using CRISPR-associated transposase elements (CASTs) offers powerful capabilities for genome engineering. The large single effector Cas12k CAST examples evolved from a minimal TnpB nuclease protein. Here, we engineer a de novo RNA-guided transposition systems in bacteria, where the single guide RNA effector components are repurposed nuclease-dead TnpB-family proteins. These compact systems mediate high-efficiency guide-RNA-directed DNA insertion with preserved orientation control, target immunity, and release of a host factor requirement and can be paired with an exonuclease domain to mediate cut-and-paste transposition. In this engineered context, the TnpB derivatives show features not predicted from the original enzymes, suggesting untapped avenues for improvement. In parallel, we show that mutations at the TniQ-TnsC interface in the Cas12k CAST system selectively attenuate off-site insertions while enhancing on-site activity. These results establish how Cas12 proteins and antecedent TnpB proteins can be engineered for high performance and specificity with guide-RNA-directed systems.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"59 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148980615","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}

引用次数: 0

Yeast Rad55-Rad57-SHU paralog complex dynamically promotes Rad51 filament formation. 酵母Rad55-Rad57-SHU平行复合体动态促进Rad51细丝的形成。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-17 Epub Date: 2026-07-21 DOI: 10.1016/j.molcel.2026.06.045

Christopher W Koo, Steven K Gore, Soo Y Ro, Jie Liu, Christine Yu, Caleigh M Azumaya, Bobby Brillantes, Inna Zilberleyb, Henry Chen, Mariam B Rafiqzada, Lyra Garcia Sanchez, Wolf-Dietrich Heyer, Claudio Ciferri, Stanislau Yatskevich

{"title":"Yeast Rad55-Rad57-SHU paralog complex dynamically promotes Rad51 filament formation.","authors":"Christopher W Koo, Steven K Gore, Soo Y Ro, Jie Liu, Christine Yu, Caleigh M Azumaya, Bobby Brillantes, Inna Zilberleyb, Henry Chen, Mariam B Rafiqzada, Lyra Garcia Sanchez, Wolf-Dietrich Heyer, Claudio Ciferri, Stanislau Yatskevich","doi":"10.1016/j.molcel.2026.06.045","DOIUrl":"10.1016/j.molcel.2026.06.045","url":null,"abstract":"Homologous recombination (HR) is an important DNA repair pathway that safeguards genome integrity. During HR, the Rad51 nucleoprotein filaments catalyze strand invasion into a homologous duplex DNA. Filament formation requires a conserved family of Rad51 paralogs that act as tumor suppressors in humans. By capturing six distinct states using cryo-electron microscopy, we reveal that the Saccharomyces cerevisiae Rad51 paralog complex, composed of the Rad55-Rad57 heterodimer and the SHU (Psy3-Csm2-Shu1-Shu2) complex, selectively brings Rad51 to single-stranded DNA to seed filament formation. Rad51 itself is a transient yet integral component of this machinery which binds along the Rad57 subunit to complete a high-affinity DNA-binding site. We also uncover a dual-nucleotide regulatory mechanism: a structural ADP molecule stabilizes the complex, while a second, catalytic ATPase site at the Rad57-Rad51 interface promotes the release of the paralog complex. These structural and mechanistic features provide a blueprint for understanding the function of Rad51 paralogs across eukaryotes.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3639-3654.e13"},"PeriodicalIF":16.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549806","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}

引用次数: 0

Oriented binding of transcription factors to nucleosomes remodels chromatin at human promoters. 转录因子与核小体的定向结合重塑了人类启动子的染色质。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-17 Epub Date: 2026-08-28 DOI: 10.1016/j.molcel.2026.08.005

Tianyi Xiao, Caillan Crowe-McAuliffe, Moritz Ochmann, Tushar Warrier, Yepeng Du, Tianyun Hou, Siwei Zou, Yinan Chen, Fangjie Zhu, Dan Zhang, Fatemeh Seyednasrollah, Kimmo Palin, Leena Salmela, Maria Osmala, Sakari Vanharanta, Ekaterina Morgunova, Patrick Cramer, Connor Rogerson, Christian Dienemann, Jussi Taipale

{"title":"Oriented binding of transcription factors to nucleosomes remodels chromatin at human promoters.","authors":"Tianyi Xiao, Caillan Crowe-McAuliffe, Moritz Ochmann, Tushar Warrier, Yepeng Du, Tianyun Hou, Siwei Zou, Yinan Chen, Fangjie Zhu, Dan Zhang, Fatemeh Seyednasrollah, Kimmo Palin, Leena Salmela, Maria Osmala, Sakari Vanharanta, Ekaterina Morgunova, Patrick Cramer, Connor Rogerson, Christian Dienemann, Jussi Taipale","doi":"10.1016/j.molcel.2026.08.005","DOIUrl":"10.1016/j.molcel.2026.08.005","url":null,"abstract":"Transcription factors (TFs) can access nucleosomes via five distinct modes: gyre-spanning, periodic-binding, dyad-binding, and end-binding modes as well as an oriented binding mode, where the TF binding motif shows orientational preference relative to the nucleosome. Here, we report the first structure of an oriented TF:nucleosome complex, where two ELF2 proteins bind to a double motif located at superhelical location +4, unwinding four helical turns of DNA from the nucleosome. We further show that unlike previously described pioneer factors, ELF2 is able to occupy all of its unmethylated, high-affinity double motifs in vivo. Motifs of ELF2 and another oriented nucleosome binder, YY1, are highly enriched downstream of transcription start sites (TSSs) of highly expressed genes, with the motifs oriented in such a way that the TSS becomes accessible upon TF binding. Our results suggest that oriented binding may be generally important for high transcriptional activity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3712-3724.e8"},"PeriodicalIF":16.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850916","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}

引用次数: 0

A splicing checkpoint licenses resistosome assembly 剪接检查点允许抵抗体组装

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-17 DOI: 10.1016/j.molcel.2026.08.020

Ruth Norkor Annang,Shuting Sun,Jonathan D.G. Jones

引用次数: 0

How to grow a filament: Lessons from the RAD51 paralogs toolbox 如何生长灯丝：从RAD51类比工具箱的教训

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-17 DOI: 10.1016/j.molcel.2026.07.037

Luca Pellegrini

引用次数: 0

HoT auto-blinking probes enable real-time, super-resolution chromatin imaging in live cells and tissues. HoT自动闪烁探针可实现活细胞和组织的实时、超分辨率染色质成像。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-17 Epub Date: 2026-08-28 DOI: 10.1016/j.molcel.2026.08.010

Aiping Wang, Shanshan Liu, Heng Shi, Mikhail Rotkevich, Carlotta Viana, Hui Zhong, Limei Zhong, Lingkuan Meng, Yanwu Li, Guirong Chen, Xiaoming Zhu, Zhenzhen Ma, Bing Fu, Alvaro Castells-Garcia, Jie Zhang, Hongyan Sun, Maria Pia Cosma

{"title":"HoT auto-blinking probes enable real-time, super-resolution chromatin imaging in live cells and tissues.","authors":"Aiping Wang, Shanshan Liu, Heng Shi, Mikhail Rotkevich, Carlotta Viana, Hui Zhong, Limei Zhong, Lingkuan Meng, Yanwu Li, Guirong Chen, Xiaoming Zhu, Zhenzhen Ma, Bing Fu, Alvaro Castells-Garcia, Jie Zhang, Hongyan Sun, Maria Pia Cosma","doi":"10.1016/j.molcel.2026.08.010","DOIUrl":"10.1016/j.molcel.2026.08.010","url":null,"abstract":"Single-molecule localization microscopy (SMLM) enables visualization of chromatin architecture at nanoscale resolution. However, high-performance DNA probes suitable for SMLM in both live cells and tissues remain limited. We developed Hoechst-6-Carboxytetramethylrhodamine (6-TAMRA) derivative (HoT) probes-rhodamine-based derivatives conjugated to a Hoechst moiety-through structural fine-tuning of rhodamine spirocyclization. HoTs are self-assembling, auto-blinking probes with excellent photostability and high temporal resolution. They permeate live cells, enabling long-term, real-time nanoscopic chromatin imaging in live and fixed cells and in tissue sections. In live cells, we identified nanoscale features in the 3D organization of chromatin and quantified DNA fiber kinetics at high resolution. We quantified DNA compaction in single cells within retinal and colon cancer sections. OligoSTORM (stochastic optical reconstruction microscopy)-labeled gene loci can be visualized and measured within their HoT-labeled chromatin footprints. Our work provides powerful tools for investigating chromatin structure and functions in living cells and tissues, with applications ranging from cancer diagnosis to retinal regeneration.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3840-3855.e8"},"PeriodicalIF":16.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850866","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}

引用次数: 0

Combinatorial deep mutational scanning uncovers protein superbinders and molecular determinants of epistasis 组合深度突变扫描揭示了蛋白质超结合物和上位性的分子决定因素

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-17 DOI: 10.1016/j.molcel.2026.08.017

Mingxuan Jiang,Mohan Sun,Nuo Cheng,Mihkel Örd,Teresa L. Augustin,Allyson Li,Neel H. Shah,Jesse Rinehart,Helen R. Mott,Pau Creixell

{"title":"Combinatorial deep mutational scanning uncovers protein superbinders and molecular determinants of epistasis","authors":"Mingxuan Jiang,Mohan Sun,Nuo Cheng,Mihkel Örd,Teresa L. Augustin,Allyson Li,Neel H. Shah,Jesse Rinehart,Helen R. Mott,Pau Creixell","doi":"10.1016/j.molcel.2026.08.017","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.017","url":null,"abstract":"Traditional deep mutational scanning (DMS) encodes every single amino-acid substitution from a wild-type sequence. We hypothesize that combinatorial DMS (CDMS) libraries, incorporating all mutations in all combinations, can enable the discovery of high-affinity protein (super)binders by capturing epistatic, non-linear amino-acid interactions. Here, we introduce origin-independent and context-exhaustive high-throughput integration of combinatorial DMS libraries (ORCHID), which systematically maps regions of wild-type-independent epistasis across all mutational contexts and trajectories. For benchmarking, we build a high-throughput peptide display assay measuring PIN1WW-domain affinity for a CDMS peptide library containing phosphoserine via amber codon suppression. ORCHID raises prediction accuracy by 45% over non-epistatic models. We identify and structurally characterize two epistatic superbinders, SPY-tide and LYR-tide, binding 3- to 5-fold tighter than current optimal PIN1WW-domain binders through “fold-and-turn” and register-shifted conformational changes. We also identify two molecular determinants of epistasis, PIN1F25 and PIN1R14, that natively encode non-linear binding and, when mutated, abolish it. Hence, natural proteins recognize peptides non-linearly, offering opportunities for improved binder design.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"59 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148980616","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}

引用次数: 0