Nature Structural & Molecular Biology最新文献_第9页

Visualizing chaperone-mediated multistep assembly of the human 20S proteasome 可视化伴侣介导的人类 20S 蛋白酶体多步骤组装

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-04-10 DOI: 10.1038/s41594-024-01268-9

Frank Adolf, Jiale Du, Ellen A. Goodall, Richard M. Walsh Jr, Shaun Rawson, Susanne von Gronau, J. Wade Harper, John Hanna, Brenda A. Schulman

{"title":"Visualizing chaperone-mediated multistep assembly of the human 20S proteasome","authors":"Frank Adolf, Jiale Du, Ellen A. Goodall, Richard M. Walsh Jr, Shaun Rawson, Susanne von Gronau, J. Wade Harper, John Hanna, Brenda A. Schulman","doi":"10.1038/s41594-024-01268-9","DOIUrl":"10.1038/s41594-024-01268-9","url":null,"abstract":"Dedicated assembly factors orchestrate the stepwise production of many molecular machines, including the 28-subunit proteasome core particle (CP) that mediates protein degradation. Here we report cryo-electron microscopy reconstructions of seven recombinant human subcomplexes that visualize all five chaperones and the three active site propeptides across a wide swath of the assembly pathway. Comparison of these chaperone-bound intermediates and a matching mature CP reveals molecular mechanisms determining the order of successive subunit additions, as well as how proteasome subcomplexes and assembly factors structurally adapt upon progressive subunit incorporation to stabilize intermediates, facilitate the formation of subsequent intermediates and ultimately rearrange to coordinate proteolytic activation with gated access to active sites. This work establishes a methodologic approach for structural analysis of multiprotein complex assembly intermediates, illuminates specific functions of assembly factors and reveals conceptual principles underlying human proteasome biogenesis, thus providing an explanation for many previous biochemical and genetic observations. Precise protease positioning and gating of the proteasome core require the ordered assembly of 28 subunits. Cryo-EM structures of seven intermediates visualize five dedicated chaperones and three propeptides mediating step-by-step assembly of the human 20S proteasome.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01268-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140541602","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}

引用次数: 0

Structure of adenylyl cyclase 5 in complex with Gβγ offers insights into ADCY5-related dyskinesia 腺苷酸环化酶 5 与 Gβγ 复合物的结构为了解 ADCY5 相关运动障碍提供了思路

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-04-08 DOI: 10.1038/s41594-024-01263-0

Yu-Chen Yen, Yong Li, Chun-Liang Chen, Thomas Klose, Val J. Watts, Carmen W. Dessauer, John J. G. Tesmer

{"title":"Structure of adenylyl cyclase 5 in complex with Gβγ offers insights into ADCY5-related dyskinesia","authors":"Yu-Chen Yen, Yong Li, Chun-Liang Chen, Thomas Klose, Val J. Watts, Carmen W. Dessauer, John J. G. Tesmer","doi":"10.1038/s41594-024-01263-0","DOIUrl":"10.1038/s41594-024-01263-0","url":null,"abstract":"The nine different membrane-anchored adenylyl cyclase isoforms (AC1–9) in mammals are stimulated by the heterotrimeric G protein, Gαs, but their response to Gβγ regulation is isoform specific. In the present study, we report cryo-electron microscope structures of ligand-free AC5 in complex with Gβγ and a dimeric form of AC5 that could be involved in its regulation. Gβγ binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C1b) that is known to be a hub for isoform-specific regulation. We confirmed the Gβγ interaction with both purified proteins and cell-based assays. Gain-of-function mutations in AC5 associated with human familial dyskinesia are located at the interface of AC5 with Gβγ and show reduced conditional activation by Gβγ, emphasizing the importance of the observed interaction for motor function in humans. We propose a molecular mechanism wherein Gβγ either prevents dimerization of AC5 or allosterically modulates the coiled-coil domain, and hence the catalytic core. As our mechanistic understanding of how individual AC isoforms are uniquely regulated is limited, studies such as this may provide new avenues for isoform-specific drug development. The authors describe the structure of an adenylyl cyclase 5 and Gβγ complex, which potentially influences a neural signalling pathway modulating motor function. Mutations in the Gβγ binding site on AC5 are linked to heritable forms of dyskinesia.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534391","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

Transport mechanism of presynaptic high-affinity choline uptake by CHT1 CHT1 对突触前高亲和性胆碱摄取的转运机制

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-04-08 DOI: 10.1038/s41594-024-01259-w

Yunlong Qiu, Yiwei Gao, Bo Huang, Qinru Bai, Yan Zhao

{"title":"Transport mechanism of presynaptic high-affinity choline uptake by CHT1","authors":"Yunlong Qiu, Yiwei Gao, Bo Huang, Qinru Bai, Yan Zhao","doi":"10.1038/s41594-024-01259-w","DOIUrl":"10.1038/s41594-024-01259-w","url":null,"abstract":"Choline is a vital nutrient and a precursor for the biosynthesis of essential metabolites, including acetylcholine (ACh), that play a central role in fetal development, especially in the brain. In cholinergic neurons, the high-affinity choline transporter (CHT1) provides an extraordinarily efficient reuptake mechanism to reutilize choline derived from intrasynaptical ACh hydrolysis and maintain ACh synthesis in the presynapse. Here, we determined structures of human CHT1 in three discrete states: the outward-facing state bound with the competitive inhibitor hemicholinium-3 (HC-3); the inward-facing occluded state bound with the substrate choline; and the inward-facing apo open state. Our structures and functional characterizations elucidate how the inhibitor and substrate are recognized. Moreover, our findings shed light on conformational changes when transitioning from an outward-facing to an inward-facing state and establish a framework for understanding the transport cycle, which relies on the stabilization of the outward-facing state by a short intracellular helix, IH1. The authors report the structures of human CHT1 in the outward-open, inward-occluded and inward-open states, reveal the mechanism of HC-3 inhibition and choline recognition and elucidate the regulatory role of the intracellular helix IH1.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534383","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

Author Correction: Structural basis for partial agonism in 5-HT3A receptors 作者更正：5-HT3A 受体部分激动的结构基础

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-04-05 DOI: 10.1038/s41594-024-01306-6

Kevin Felt, Madeleine Stauffer, Leslie Salas-Estrada, Peter R. Guzzo, Dejian Xie, Jinkun Huang, Marta Filizola, Sudha Chakrapani

引用次数: 0

SCAF1 drives the compositional diversity of mammalian respirasomes SCAF1 驱动哺乳动物呼吸体的组成多样性

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-04-04 DOI: 10.1038/s41594-024-01255-0

Irene Vercellino, Leonid A. Sazanov

{"title":"SCAF1 drives the compositional diversity of mammalian respirasomes","authors":"Irene Vercellino, Leonid A. Sazanov","doi":"10.1038/s41594-024-01255-0","DOIUrl":"10.1038/s41594-024-01255-0","url":null,"abstract":"Supercomplexes of the respiratory chain are established constituents of the oxidative phosphorylation system, but their role in mammalian metabolism has been hotly debated. Although recent studies have shown that different tissues/organs are equipped with specific sets of supercomplexes, depending on their metabolic needs, the notion that supercomplexes have a role in the regulation of metabolism has been challenged. However, irrespective of the mechanistic conclusions, the composition of various high molecular weight supercomplexes remains uncertain. Here, using cryogenic electron microscopy, we demonstrate that mammalian (mouse) tissues contain three defined types of ‘respirasome’, supercomplexes made of CI, CIII2 and CIV. The stoichiometry and position of CIV differs in the three respirasomes, of which only one contains the supercomplex-associated factor SCAF1, whose involvement in respirasome formation has long been contended. Our structures confirm that the ‘canonical’ respirasome (the C-respirasome, CICIII2CIV) does not contain SCAF1, which is instead associated to a different respirasome (the CS-respirasome), containing a second copy of CIV. We also identify an alternative respirasome (A-respirasome), with CIV bound to the ‘back’ of CI, instead of the ‘toe’. This structural characterization of mouse mitochondrial supercomplexes allows us to hypothesize a mechanistic basis for their specific role in different metabolic conditions. Here the authors structurally characterize respiratory supercomplexes, revealing that, in addition to the known ‘canonical’ respirasome, mammalian mitochondria contain two novel respirasome types, one of which incorporates supercomplex assembly factor SCAF1.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140346180","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 rare genetic variant biases maternal meiotic recombination toward risk of pregnancy loss 一种罕见的基因变异会使母体减数分裂重组偏向于妊娠失败的风险

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-04-03 DOI: 10.1038/s41594-024-01269-8

Sara A. Carioscia, Rajiv C. McCoy

引用次数: 0

Shifting our perspective on orphan G protein-coupled receptors 转变我们对孤儿 G 蛋白偶联受体的看法

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-04-02 DOI: 10.1038/s41594-024-01270-1

Nicola J. Smith, Fiona Murray

引用次数: 0

Molecular basis for Gβγ-mediated activation of phosphoinositide 3-kinase γ Gβγ 介导的磷酸肌醇 3- 激酶 γ 激活的分子基础

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-04-02 DOI: 10.1038/s41594-024-01265-y

Chun-Liang Chen, Ramizah Syahirah, Sandeep K. Ravala, Yu-Chen Yen, Thomas Klose, Qing Deng, John J. G. Tesmer

{"title":"Molecular basis for Gβγ-mediated activation of phosphoinositide 3-kinase γ","authors":"Chun-Liang Chen, Ramizah Syahirah, Sandeep K. Ravala, Yu-Chen Yen, Thomas Klose, Qing Deng, John J. G. Tesmer","doi":"10.1038/s41594-024-01265-y","DOIUrl":"10.1038/s41594-024-01265-y","url":null,"abstract":"The conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate by phosphoinositide 3-kinase γ (PI3Kγ) is critical for neutrophil chemotaxis and cancer metastasis. PI3Kγ is activated by Gβγ heterodimers released from G protein-coupled receptors responding to extracellular signals. Here we determined cryo-electron microscopy structures of Sus scrofa PI3Kγ–human Gβγ complexes in the presence of substrates/analogs, revealing two Gβγ binding sites: one on the p110γ helical domain and another on the p101 C-terminal domain. Comparison with PI3Kγ alone reveals conformational changes in the kinase domain upon Gβγ binding that are similar to Ras·GTP-induced changes. Assays of variants perturbing the Gβγ binding sites and interdomain contacts altered by Gβγ binding suggest that Gβγ recruits the enzyme to membranes and allosterically regulates activity via both sites. Studies of zebrafish neutrophil migration align with these findings, paving the way for in-depth investigation of Gβγ-mediated activation mechanisms in this enzyme family and drug development for PI3Kγ. Phosphoinositide 3-kinase γ plays critical roles in neutrophil chemotaxis and cancer metastasis. Here, using cryo-EM and functional studies, the authors reveal how two molecules of a key activator, Gβγ, bind to and alter the conformation of the enzyme.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140340656","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

Cryo-EM structures of amyloid-β and tau filaments in Down syndrome 唐氏综合征中淀粉样蛋白-β和 tau 纤维的冷冻电镜结构

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-03-29 DOI: 10.1038/s41594-024-01252-3

Anllely Fernandez, Md Rejaul Hoq, Grace I. Hallinan, Daoyi Li, Sakshibeedu R. Bharath, Frank S. Vago, Xiaoqi Zhang, Kadir A. Ozcan, Kathy L. Newell, Holly J. Garringer, Wen Jiang, Bernardino Ghetti, Ruben Vidal

{"title":"Cryo-EM structures of amyloid-β and tau filaments in Down syndrome","authors":"Anllely Fernandez, Md Rejaul Hoq, Grace I. Hallinan, Daoyi Li, Sakshibeedu R. Bharath, Frank S. Vago, Xiaoqi Zhang, Kadir A. Ozcan, Kathy L. Newell, Holly J. Garringer, Wen Jiang, Bernardino Ghetti, Ruben Vidal","doi":"10.1038/s41594-024-01252-3","DOIUrl":"10.1038/s41594-024-01252-3","url":null,"abstract":"Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains. We found two Aβ40 filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ42 filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials. Here, using cryo-EM, authors reveal that amyloid-β and tau are identical in Alzheimer disease and Down syndrome. This has implications for assessing whether adults with Down syndrome could be included in Alzheimer disease clinical trials.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01252-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140321972","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}

引用次数: 0

High-resolution structures of amyloid-β and tau aggregates in individuals with Down syndrome 唐氏综合征患者体内淀粉样蛋白-β和tau聚集体的高分辨率结构

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-03-29 DOI: 10.1038/s41594-024-01254-1

引用次数: 0