首页 > 最新文献

Structure最新文献

英文 中文
AI decodes CNNM Na+/Mg2+ exchange 人工智能解码CNNM Na+/Mg2+交换
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-02 DOI: 10.1016/j.str.2024.12.006
Thushara Nethramangalath, Loren W. Runnels
In this issue of Structure, Ma et al.1 apply the artificial intelligence system AlphaFold2, which was designed to predict three-dimensional protein structures from amino acid sequences with atomic accuracy, to model the conformal dynamics of the prokaryotic TpCorC and human CNNM2 and CNNM4 transporters, providing mechanistic insight into how sodium drives magnesium efflux.
在本期的《结构》杂志中,Ma等人1应用人工智能系统AlphaFold2,该系统旨在以原子精度预测氨基酸序列的三维蛋白质结构,来模拟原核TpCorC和人类CNNM2和CNNM4转运体的保形动力学,为钠如何驱动镁外排提供了机制见解。
{"title":"AI decodes CNNM Na+/Mg2+ exchange","authors":"Thushara Nethramangalath, Loren W. Runnels","doi":"10.1016/j.str.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.006","url":null,"abstract":"In this issue of <em>Structure</em>, Ma et al.<span><span><sup>1</sup></span></span> apply the artificial intelligence system AlphaFold2, which was designed to predict three-dimensional protein structures from amino acid sequences with atomic accuracy, to model the conformal dynamics of the prokaryotic TpCorC and human CNNM2 and CNNM4 transporters, providing mechanistic insight into how sodium drives magnesium efflux.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"25 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
It takes two to tango: The second membrane-binding site in peripheral proteins 探戈需要两个:外周蛋白的第二个膜结合位点
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-02 DOI: 10.1016/j.str.2024.12.007
Anand Srivastavava
In this issue of Structure, Soteriou et al.1 use cell biology, in vitro reconstitution approaches, and molecular dynamics (MD) simulations to characterize the membrane association of AKT1. The authors show that the AKT1 pleckstrin homology domain contains two essential and cooperative PI(3,4,5)P3-binding sites that enable stable membrane binding of AKT1 in the requisite orientation required for effective downstream signaling.
在本期《结构》杂志中,Soteriou等人利用细胞生物学、体外重构方法和分子动力学(MD)模拟来表征AKT1的膜关联。作者表明,AKT1 pleckstrin同源结构域包含两个必不可少的协同PI(3,4,5) p3结合位点,使AKT1在有效的下游信号传递所需的必要方向上稳定的膜结合。
{"title":"It takes two to tango: The second membrane-binding site in peripheral proteins","authors":"Anand Srivastavava","doi":"10.1016/j.str.2024.12.007","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.007","url":null,"abstract":"In this issue of <em>Structure</em>, Soteriou et al.<span><span><sup>1</sup></span></span> use cell biology, <em>in vitro</em> reconstitution approaches, and molecular dynamics (MD) simulations to characterize the membrane association of AKT1. The authors show that the AKT1 pleckstrin homology domain contains two essential and cooperative PI(3,4,5)P<sub>3</sub>-binding sites that enable stable membrane binding of AKT1 in the requisite orientation required for effective downstream signaling.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"66 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Lysozyme revisited 溶菌酶重新审视
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-02 DOI: 10.1016/j.str.2024.12.005
Esko Oksanen
Lysozyme is a model system for crystallographers. In this issue of Structure, Ramos et al. report atomic resolution neutron structures of lysozyme, which unambiguously show the protonation states and hydrogen-bonding networks of the active site. This resolves mechanistic questions that have been debated for decades and provides a unique view to a protein at atomic detail.
溶菌酶是晶体学家的模型系统。在本期的Structure中,Ramos等人报道了溶菌酶的原子分辨率中子结构,明确地显示了活性位点的质子化状态和氢键网络。这解决了争论了几十年的机械问题,并为蛋白质的原子细节提供了独特的视角。
{"title":"Lysozyme revisited","authors":"Esko Oksanen","doi":"10.1016/j.str.2024.12.005","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.005","url":null,"abstract":"Lysozyme is a model system for crystallographers. In this issue of <em>Structure</em>, Ramos et al. report atomic resolution neutron structures of lysozyme, which unambiguously show the protonation states and hydrogen-bonding networks of the active site. This resolves mechanistic questions that have been debated for decades and provides a unique view to a protein at atomic detail.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"23 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
The structure and assembly of the hetero-octameric BLOC-one-related complex 异八聚体block - 1相关配合物的结构与组装
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-30 DOI: 10.1016/j.str.2024.12.001
Xuan Ge, Jinqi Ren, Kewei Gu, Weibin Gong, Kang Shen, Wei Feng
BORC (BLOC-one-related complex) is a hetero-octameric complex, consisting of eight coiled-coil proteins (BORCS1–8). BORC controls lysosomal and synaptic vesicle transport and positioning by recruiting ARL8. The structural mechanisms underlying BORC assembly and ARL8 activation remain unclear. Here, we reconstitute and construct the structural model of this hetero-octameric complex. We find that BORC adopts an extended, rod-like structure made of coiled coils. Two hemicomplexes, each containing four subunits, are joined end-to-end to form the holocomplex. Within each hemicomplex, BORCS1/4/6/8 or BORCS2/3/5/7 assembles into similar helical bundles. We further study how BORC is built and discover a hierarchical assembly process in which BORCS1/2/3/5 forms the core scaffold and recruits other subunits. Mutations in the inter-hemicomplex interfaces result in two hemicomplexes. The association of ARL8 may require the proper assembly of BORC and is primarily mediated by BORCS5. These results provide guidance for further understanding of the biology of BORC.
BORC (block - 1 -related complex)是一种异八聚体复合物,由8个螺旋状蛋白组成(BORCS1-8)。BORC通过募集ARL8控制溶酶体和突触囊泡的转运和定位。BORC组装和ARL8激活的结构机制尚不清楚。在此,我们重构并构建了这种杂八聚配合物的结构模型。我们发现BORC采用了一种由线圈组成的延伸棒状结构。两个半配合物,每个包含四个亚基,端到端连接形成全配合物。在每个半复合物中,BORCS1/4/6/8或BORCS2/3/5/7组装成类似的螺旋束。我们进一步研究了BORC是如何构建的,发现了BORCS1/2/3/5形成核心支架并招募其他亚基的分层组装过程。半复合物界面的突变产生两个半复合物。ARL8的关联可能需要BORC的适当组装,并且主要由BORCS5介导。这些结果为进一步认识BORC的生物学特性提供了指导。
{"title":"The structure and assembly of the hetero-octameric BLOC-one-related complex","authors":"Xuan Ge, Jinqi Ren, Kewei Gu, Weibin Gong, Kang Shen, Wei Feng","doi":"10.1016/j.str.2024.12.001","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.001","url":null,"abstract":"BORC (BLOC-one-related complex) is a hetero-octameric complex, consisting of eight coiled-coil proteins (BORCS1–8). BORC controls lysosomal and synaptic vesicle transport and positioning by recruiting ARL8. The structural mechanisms underlying BORC assembly and ARL8 activation remain unclear. Here, we reconstitute and construct the structural model of this hetero-octameric complex. We find that BORC adopts an extended, rod-like structure made of coiled coils. Two hemicomplexes, each containing four subunits, are joined end-to-end to form the holocomplex. Within each hemicomplex, BORCS1/4/6/8 or BORCS2/3/5/7 assembles into similar helical bundles. We further study how BORC is built and discover a hierarchical assembly process in which BORCS1/2/3/5 forms the core scaffold and recruits other subunits. Mutations in the inter-hemicomplex interfaces result in two hemicomplexes. The association of ARL8 may require the proper assembly of BORC and is primarily mediated by BORCS5. These results provide guidance for further understanding of the biology of BORC.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"168 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Physicochemical features of subunit interfaces and their role in self-assembly across the ferritin superfamily 亚基界面的物理化学特征及其在铁蛋白超家族自组装中的作用
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-30 DOI: 10.1016/j.str.2024.12.004
, Soumyananda Chakraborti, Sucharita Dey
Ferritins are ubiquitous and play a critical role in iron homeostasis. They are classified into four main subfamilies: classical, bacterial, bacterioferritin, and Dps. These are characterized by subunits with a four-helical bundle domain and interact through three distinct regions—one antiparallel interface (IntA) and two perpendicular interfaces (IntB and IntC), collectively forming a cage-like structure. Here, we attempt to characterize the variability of these interfaces across subfamilies. We found that IntA is essential for the dimeric unit assembly and is likely to assemble first, followed by the smaller interfaces of IntB and IntC (in any order), which are crucial for cage formation. These interfaces are unique in that they are less packed, although chemically stable, and their size lies between that of protein-protein complex and obligate homodimers. This study provides a detailed exploration of the ferritin interfaces, offering insights into their assembly and their importance as carrier proteins.
铁蛋白普遍存在,在铁稳态中起关键作用。它们被分为四个主要亚科:经典、细菌、细菌铁蛋白和Dps。它们的特征是具有四螺旋束结构域的亚基,并通过三个不同的区域相互作用——一个反平行界面(IntA)和两个垂直界面(IntB和IntC),共同形成一个笼状结构。在这里,我们试图描述跨亚族这些界面的可变性。我们发现IntA对于二聚体单元的组装至关重要,并且可能首先组装,其次是IntB和IntC的较小界面(以任何顺序),这对于笼形形成至关重要。这些界面的独特之处在于,虽然化学性质稳定,但它们的包裹较少,它们的大小介于蛋白质-蛋白质复合物和专性二聚体之间。本研究提供了对铁蛋白界面的详细探索,提供了对其组装及其作为载体蛋白的重要性的见解。
{"title":"Physicochemical features of subunit interfaces and their role in self-assembly across the ferritin superfamily","authors":", Soumyananda Chakraborti, Sucharita Dey","doi":"10.1016/j.str.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.004","url":null,"abstract":"Ferritins are ubiquitous and play a critical role in iron homeostasis. They are classified into four main subfamilies: classical, bacterial, bacterioferritin, and Dps. These are characterized by subunits with a four-helical bundle domain and interact through three distinct regions—one antiparallel interface (IntA) and two perpendicular interfaces (IntB and IntC), collectively forming a cage-like structure. Here, we attempt to characterize the variability of these interfaces across subfamilies. We found that IntA is essential for the dimeric unit assembly and is likely to assemble first, followed by the smaller interfaces of IntB and IntC (in any order), which are crucial for cage formation. These interfaces are unique in that they are less packed, although chemically stable, and their size lies between that of protein-protein complex and obligate homodimers. This study provides a detailed exploration of the ferritin interfaces, offering insights into their assembly and their importance as carrier proteins.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"65 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Structural insights into the biochemical mechanism of the E2/E3 hybrid enzyme UBE2O 从结构上揭示 E2/E3 混合酶 UBE2O 的生化机制
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-30 DOI: 10.1016/j.str.2024.12.002
Hao Huang, Wenning Zhu, Bin Huang, Ziyang Fu, Yuxian Xiong, Dan Cao, Yuxin Ye, Qing Chang, Wenqi Li, Long Li, Huan Zhou, Xiaogang Niu, Wei Zhang
The E2/E3 hybrid enzyme UBE2O plays important roles in key biological events, but its autoubiquitination mechanism remains largely unclear. In this study, we determined the crystal structures of full-length (FL) UBE2O from Trametes pubescens (tp) and its ubiquitin-conjugating (UBC) domain. The dimeric FL-tpUBE2O structure revealed interdomain interactions between the conserved regions (CR1-CR2) and UBC. The dimeric intermolecular and canonical ubiquitin/UBC interactions are mechanistically important for UBE2O functions in catalyzing the formation of free polyubiquitin chains and substrate ubiquitination. Beyond dimerization, autoubiquitination within the CR1-CR2 domain also regulates tpUBE2O activity. Additionally, we show that tpUBE2O catalyzes the formation of all seven types of polyubiquitin chains in vitro. The CR1-CR2/UBC and canonical ubiquitin/UBC interactions are important for the polyubiquitination of AMP-activated protein kinase α2 (AMPKα2) by human UBE2O (hUBE2O), which leads to tumorigenesis. These structural insights lay the groundwork for understanding UBE2O’s mechanisms and developing structure-based therapeutics targeting UBE2O.
E2/E3杂交酶UBE2O在关键生物学事件中发挥重要作用,但其自泛素化机制尚不清楚。在这项研究中,我们确定了从Trametes pubescens (tp)中提取的全长(FL) ube20及其泛素偶联(UBC)结构域的晶体结构。二聚体FL-tpUBE2O结构揭示了保守区域(CR1-CR2)和UBC之间的域间相互作用。二聚体分子间和典型泛素/UBC相互作用对ube20催化游离多泛素链的形成和底物泛素化的功能具有重要的机制意义。除了二聚化外,CR1-CR2结构域内的自泛素化也调节tpUBE2O活性。此外,我们发现tpube20在体外催化所有七种多泛素链的形成。CR1-CR2/UBC和典型泛素/UBC相互作用对于人UBE2O (hUBE2O)对amp活化的蛋白激酶α2 (AMPKα2)的多泛素化至关重要,从而导致肿瘤的发生。这些结构见解为理解UBE2O的机制和开发针对UBE2O的基于结构的治疗方法奠定了基础。
{"title":"Structural insights into the biochemical mechanism of the E2/E3 hybrid enzyme UBE2O","authors":"Hao Huang, Wenning Zhu, Bin Huang, Ziyang Fu, Yuxian Xiong, Dan Cao, Yuxin Ye, Qing Chang, Wenqi Li, Long Li, Huan Zhou, Xiaogang Niu, Wei Zhang","doi":"10.1016/j.str.2024.12.002","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.002","url":null,"abstract":"The E2/E3 hybrid enzyme UBE2O plays important roles in key biological events, but its autoubiquitination mechanism remains largely unclear. In this study, we determined the crystal structures of full-length (FL) UBE2O from <em>Trametes pubescens</em> (tp) and its ubiquitin-conjugating (UBC) domain. The dimeric FL-tpUBE2O structure revealed interdomain interactions between the conserved regions (CR1-CR2) and UBC. The dimeric intermolecular and canonical ubiquitin/UBC interactions are mechanistically important for UBE2O functions in catalyzing the formation of free polyubiquitin chains and substrate ubiquitination. Beyond dimerization, autoubiquitination within the CR1-CR2 domain also regulates tpUBE2O activity. Additionally, we show that tpUBE2O catalyzes the formation of all seven types of polyubiquitin chains <em>in vitro</em>. The CR1-CR2/UBC and canonical ubiquitin/UBC interactions are important for the polyubiquitination of AMP-activated protein kinase α2 (AMPKα2) by human UBE2O (hUBE2O), which leads to tumorigenesis. These structural insights lay the groundwork for understanding UBE2O’s mechanisms and developing structure-based therapeutics targeting UBE2O.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"81 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
The structures of the peptide transporters SLC15A3 and SLC15A4 reveal the recognition mechanisms for substrate and TASL 肽转运体SLC15A3和SLC15A4的结构揭示了对底物和TASL的识别机制
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-23 DOI: 10.1016/j.str.2024.11.019
Zhikuan Zhang, Shota Kasai, Kentaro Sakaniwa, Akiko Fujimura, Umeharu Ohto, Toshiyuki Shimizu
The solute carrier family 15 members 3 and 4 (SLC15A3 and SLC15A4) are closely related endolysosomal peptide transporters that transport free histidine and certain dipeptides from the lumen to cytosol. Besides, SLC15A4 also functions as a scaffold protein for the recruitment of the adapter TASL for interferon regulatory factor 5 (IRF5) activation downstream of innate immune TLR7-9 signaling. However, the molecular basis for the substrate recognition and TASL recruitment by these membrane proteins is not well understood. Here, we report the cryoelectron microscopy (cryo-EM) structure of apo SLC15A3 and structures of SLC15A4 in the absence or presence of the substrate, revealing the specific dipeptide recognition mechanism. Each SLC15A3 and SLC15A4 protomer adopts an outward-facing conformation. Furthermore, we also present the cryo-EM structure of a SLC15A4-TASL complex. The N terminal region of TASL forms a helical structure that inserts deeply into the inward-facing cavity of SLC15A4.
溶质载体家族15成员3和4 (SLC15A3和SLC15A4)是密切相关的内溶酶体肽转运体,将游离组氨酸和某些二肽从管腔运输到细胞质。此外,SLC15A4还作为支架蛋白,在先天免疫TLR7-9信号下游募集适配体TASL,激活干扰素调节因子5 (IRF5)。然而,这些膜蛋白识别底物和募集TASL的分子基础尚不清楚。在此,我们报道了载脂蛋白SLC15A3和SLC15A4在无底物或存在底物情况下的低温电镜结构,揭示了特定的二肽识别机制。每个SLC15A3和SLC15A4原聚体采用外向构象。此外,我们还展示了SLC15A4-TASL配合物的低温电镜结构。TASL的N端区域形成螺旋状结构,深入SLC15A4的内腔。
{"title":"The structures of the peptide transporters SLC15A3 and SLC15A4 reveal the recognition mechanisms for substrate and TASL","authors":"Zhikuan Zhang, Shota Kasai, Kentaro Sakaniwa, Akiko Fujimura, Umeharu Ohto, Toshiyuki Shimizu","doi":"10.1016/j.str.2024.11.019","DOIUrl":"https://doi.org/10.1016/j.str.2024.11.019","url":null,"abstract":"The solute carrier family 15 members 3 and 4 (SLC15A3 and SLC15A4) are closely related endolysosomal peptide transporters that transport free histidine and certain dipeptides from the lumen to cytosol. Besides, SLC15A4 also functions as a scaffold protein for the recruitment of the adapter TASL for interferon regulatory factor 5 (IRF5) activation downstream of innate immune TLR7-9 signaling. However, the molecular basis for the substrate recognition and TASL recruitment by these membrane proteins is not well understood. Here, we report the cryoelectron microscopy (cryo-EM) structure of apo SLC15A3 and structures of SLC15A4 in the absence or presence of the substrate, revealing the specific dipeptide recognition mechanism. Each SLC15A3 and SLC15A4 protomer adopts an outward-facing conformation. Furthermore, we also present the cryo-EM structure of a SLC15A4-TASL complex. The N terminal region of TASL forms a helical structure that inserts deeply into the inward-facing cavity of SLC15A4.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"61 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Antigen presentation by MHC-II is shaped by competitive and cooperative allosteric mechanisms of peptide exchange 抗原呈递由MHC-II形成的竞争和合作变构机制的肽交换
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-20 DOI: 10.1016/j.str.2024.11.014
Matthias Günther, Jana Sticht, Christian Freund, Thomas Höfer
Major histocompatibility complex class II (MHC-II) presents antigens to T helper cells. The spectrum of presented peptides is regulated by the exchange catalyst human leukocyte antigen DM (HLA-DM), which dissociates peptide-MHC-II complexes in the endosome. How susceptible a peptide is to HLA-DM is mechanistically not understood. Here, we present a data-driven mathematical model for the conformational landscape of MHC-II that explains the wide range of measured HLA-DM susceptibilities and predicts why some peptides are largely HLA-DM-resistant. We find that the conformational plasticity of MHC-II mediates both allosteric competition and cooperation between peptide and HLA-DM. Competition causes HLA-DM susceptibility to be proportional to the intrinsic peptide off-rate. Remarkably, diverse MHC-II allotypes with conserved HLA-DM interactions show a universal linear susceptibility function. However, HLA-DM-resistant peptides deviate from this susceptibility function; we predict resistance to be caused by fast peptide association with MHC-II. Thus, our study provides quantitative insight into peptide and MHC-II allotype parameters that shape class-II antigen presentation.
主要组织相容性复合体II类(MHC-II)向T辅助细胞呈递抗原。所述肽的光谱由交换催化剂人白细胞抗原DM (HLA-DM)调节,该催化剂在核内体中解离肽- mhc - ii复合物。肽对HLA-DM的敏感程度机制尚不清楚。在这里,我们提出了MHC-II构象景观的数据驱动数学模型,该模型解释了广泛测量的HLA-DM敏感性,并预测了为什么一些肽在很大程度上具有HLA-DM抗性。我们发现MHC-II的构象可塑性既介导了肽与HLA-DM之间的变构竞争,也介导了它们之间的合作。竞争导致HLA-DM的敏感性与内在肽的脱落率成正比。值得注意的是,具有保守HLA-DM相互作用的多种MHC-II同种异型表现出普遍的线性敏感性函数。然而,hla - dm抗性肽偏离了这种敏感性功能;我们预测耐药性是由与MHC-II的快速肽关联引起的。因此,我们的研究为形成ii类抗原呈递的肽和MHC-II异型参数提供了定量的见解。
{"title":"Antigen presentation by MHC-II is shaped by competitive and cooperative allosteric mechanisms of peptide exchange","authors":"Matthias Günther, Jana Sticht, Christian Freund, Thomas Höfer","doi":"10.1016/j.str.2024.11.014","DOIUrl":"https://doi.org/10.1016/j.str.2024.11.014","url":null,"abstract":"Major histocompatibility complex class II (MHC-II) presents antigens to T helper cells. The spectrum of presented peptides is regulated by the exchange catalyst human leukocyte antigen DM (HLA-DM), which dissociates peptide-MHC-II complexes in the endosome. How susceptible a peptide is to HLA-DM is mechanistically not understood. Here, we present a data-driven mathematical model for the conformational landscape of MHC-II that explains the wide range of measured HLA-DM susceptibilities and predicts why some peptides are largely HLA-DM-resistant. We find that the conformational plasticity of MHC-II mediates both allosteric competition and cooperation between peptide and HLA-DM. Competition causes HLA-DM susceptibility to be proportional to the intrinsic peptide off-rate. Remarkably, diverse MHC-II allotypes with conserved HLA-DM interactions show a universal linear susceptibility function. However, HLA-DM-resistant peptides deviate from this susceptibility function; we predict resistance to be caused by fast peptide association with MHC-II. Thus, our study provides quantitative insight into peptide and MHC-II allotype parameters that shape class-II antigen presentation.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"20 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Dantrolene inhibition of ryanodine receptor 1 carrying the severe malignant hyperthermia mutation Y522S visualized by cryo-EM 低温电镜观察丹trolene对携带严重恶性高热突变Y522S的ryanodine受体1的抑制作用
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-20 DOI: 10.1016/j.str.2024.11.018
Kavita A. Iyer, Takuya Kobayashi, Takashi Murayama, Montserrat Samsó
Mutations in the skeletal isoform of the ryanodine receptor 1 (RyR1) pose grave risks during anesthesia or treatment with succinylcholine muscle relaxants. These can trigger a potentially lethal malignant hyperthermia (MH) episode via intracellular calcium increase mainly from RyR1 channel leakage. Dantrolene is the only known treatment option to prevent death. The main target of dantrolene is RyR1; however, little is known about the mechanism of inhibition. Cryoelectron microscopy (cryo-EM) structures of dantrolene bound to the severe MH Y522S RyR1 mutant in the closed and open states at 2.5–3.3 Å resolution revealed that the drug binds to the channel’s cytoplasmic assembly, far from the ion gate, interacting with residues W882, W996, and R1000 in the P1 domain. The finding was validated by Ca2+ imaging and [3H]ryanodine binding in wild-type (WT) and alanine mutants. Dantrolene reduced channel opening probability by restricting the central activation module, “cooling down” the primed conformation caused by the mutation.
ryanodine受体1 (RyR1)的骨骼异构体突变在麻醉或琥珀胆碱肌肉松弛剂治疗期间会造成严重风险。这些可通过主要由RyR1通道渗漏引起的细胞内钙增加引发潜在致命的恶性高热(MH)发作。丹trolene是唯一已知的预防死亡的治疗选择。丹trolene的主要靶点是RyR1;然而,人们对其抑制机制知之甚少。在2.5-3.3 Å分辨率下,与严重MH Y522S RyR1突变体结合的丹trolene在关闭和打开状态下的冷冻电镜(cro - em)结构显示,该药物结合到远离离子门的通道细胞质组装上,与P1结构域的残基W882、W996和R1000相互作用。这一发现得到了野生型(WT)和丙氨酸突变体Ca2+成像和[3H]ryanodine结合的验证。丹trolene通过限制中心激活模块,“冷却”由突变引起的启动构象来降低通道打开概率。
{"title":"Dantrolene inhibition of ryanodine receptor 1 carrying the severe malignant hyperthermia mutation Y522S visualized by cryo-EM","authors":"Kavita A. Iyer, Takuya Kobayashi, Takashi Murayama, Montserrat Samsó","doi":"10.1016/j.str.2024.11.018","DOIUrl":"https://doi.org/10.1016/j.str.2024.11.018","url":null,"abstract":"Mutations in the skeletal isoform of the ryanodine receptor 1 (RyR1) pose grave risks during anesthesia or treatment with succinylcholine muscle relaxants. These can trigger a potentially lethal malignant hyperthermia (MH) episode via intracellular calcium increase mainly from RyR1 channel leakage. Dantrolene is the only known treatment option to prevent death. The main target of dantrolene is RyR1; however, little is known about the mechanism of inhibition. Cryoelectron microscopy (cryo-EM) structures of dantrolene bound to the severe MH Y522S RyR1 mutant in the closed and open states at 2.5–3.3 Å resolution revealed that the drug binds to the channel’s cytoplasmic assembly, far from the ion gate, interacting with residues W882, W996, and R1000 in the P1 domain. The finding was validated by Ca<sup>2+</sup> imaging and [<sup>3</sup>H]ryanodine binding in wild-type (WT) and alanine mutants. Dantrolene reduced channel opening probability by restricting the central activation module, “cooling down” the primed conformation caused by the mutation.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"112 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Systematic characterization of indel variants using a yeast-based protein folding sensor 利用酵母蛋白折叠传感器系统表征indel变异
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-19 DOI: 10.1016/j.str.2024.11.017
Sven Larsen-Ledet, Søren Lindemose, Aleksandra Panfilova, Sarah Gersing, Caroline H. Suhr, Aitana Victoria Genzor, Heleen Lanters, Sofie V. Nielsen, Kresten Lindorff-Larsen, Jakob R. Winther, Amelie Stein, Rasmus Hartmann-Petersen
Gene variants resulting in insertions or deletions of amino acid residues (indels) have important consequences for evolution and are often linked to disease, yet, compared to missense variants, the effects of indels are poorly understood and predicted. We developed a sensitive protein folding sensor based on the complementation of uracil auxotrophy in yeast by circular permutated orotate phosphoribosyltransferase (CPOP). The sensor reports on the folding of disease-linked missense variants and de-novo-designed proteins. Applying the folding sensor to a saturated library of single-residue indels in human dihydrofolate reductase (DHFR) revealed that most regions that tolerate indels are confined to internal loops, the termini, and a central α helix. Several indels are temperature sensitive, and folding is rescued upon binding to methotrexate. Rosetta and AlphaFold2 predictions correlate with the observed effects, suggesting that most indels destabilize the native fold and that these computational tools are useful for the classification of indels observed in population sequencing.
由氨基酸残基插入或缺失(indels)导致的基因变异对进化具有重要影响,而且往往与疾病有关,然而,与错义变异相比,人们对indels的影响知之甚少,也难以预测。我们开发了一种灵敏的蛋白质折叠传感器,它基于环状包被乳清酸磷酸核糖转移酶(CPOP)对酵母中尿嘧啶辅助营养的互补作用。该传感器能报告与疾病相关的错义变体和重新设计的蛋白质的折叠情况。将折叠传感器应用于人类二氢叶酸还原酶(DHFR)中的单残基吲哚饱和库,发现大多数能容忍吲哚的区域都局限于内部环路、末端和中央α螺旋。有几个嵌段对温度很敏感,在与甲氨蝶呤结合后,折叠得到了挽救。Rosetta和AlphaFold2的预测与观察到的效果相关,这表明大多数嵌合体会破坏原生折叠的稳定性,而且这些计算工具对群体测序中观察到的嵌合体分类很有用。
{"title":"Systematic characterization of indel variants using a yeast-based protein folding sensor","authors":"Sven Larsen-Ledet, Søren Lindemose, Aleksandra Panfilova, Sarah Gersing, Caroline H. Suhr, Aitana Victoria Genzor, Heleen Lanters, Sofie V. Nielsen, Kresten Lindorff-Larsen, Jakob R. Winther, Amelie Stein, Rasmus Hartmann-Petersen","doi":"10.1016/j.str.2024.11.017","DOIUrl":"https://doi.org/10.1016/j.str.2024.11.017","url":null,"abstract":"Gene variants resulting in insertions or deletions of amino acid residues (indels) have important consequences for evolution and are often linked to disease, yet, compared to missense variants, the effects of indels are poorly understood and predicted. We developed a sensitive protein folding sensor based on the complementation of uracil auxotrophy in yeast by circular permutated orotate phosphoribosyltransferase (CPOP). The sensor reports on the folding of disease-linked missense variants and <em>de</em>-<em>novo</em>-designed proteins. Applying the folding sensor to a saturated library of single-residue indels in human dihydrofolate reductase (DHFR) revealed that most regions that tolerate indels are confined to internal loops, the termini, and a central α helix. Several indels are temperature sensitive, and folding is rescued upon binding to methotrexate. Rosetta and AlphaFold2 predictions correlate with the observed effects, suggesting that most indels destabilize the native fold and that these computational tools are useful for the classification of indels observed in population sequencing.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"87 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
期刊
Structure
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1