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Visualizing Viral RNA Packaging Signals in Action 可视化病毒 RNA 包装信号的作用。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-29 DOI: 10.1016/j.jmb.2024.168765

Here we confirm, using genome-scale RNA fragments in assembly competition assays, that multiple sub-sites (Packaging Signals, PSs) across the 5′ two-thirds of the gRNA of Satellite Tobacco Necrosis Virus-1 make sequence-specific contacts to the viral CPs helping to nucleate formation of its T = 1 virus-like particle (VLP). These contacts explain why natural virions only package their positive-sense genomes. Asymmetric cryo-EM reconstructions of these VLPs suggest that interactions occur between amino acid residues in the N-terminal ends of the CP subunits and the gRNA PS loop sequences. The base-paired stems of PSs also act non-sequence-specifically by electrostatically promoting the assembly of CP trimers. Importantly, alterations in PS-CP affinity result in an asymmetric distribution of bound PSs inside VLPs, with fuller occupation of the higher affinity 5′ PS RNAs around one vertex, decreasing to an RNA-free opposite vertex within the VLP shell. This distribution suggests that gRNA folding regulates cytoplasmic genome extrusion so that the weakly bound 3′ end of the gRNA, containing the RNA polymerase binding site, extrudes first. This probably occurs after cation-loss induced swelling of the CP-shell, weakening contacts between CP subunits. These data reveal for the first time in any virus how differential PS folding propensity and CP affinities support the multiple roles genomes play in virion assembly and infection. The high degree of conservation between the CP fold of STNV-1 and those of the CPs of many other viruses suggests that these aspects of genome function will be widely shared.

在这里,我们利用基因组尺度的 RNA 片段进行了组装竞争试验,证实卫星烟草坏死病毒-1 的 gRNA 的 5́三分之二处有多个亚位点(包装信号,PSs)与病毒 CPs 发生序列特异性接触,有助于 T=1 病毒样颗粒(VLP)的核形成。这些接触解释了为什么天然病毒只包装正义基因组。这些 VLP 的非对称低温电子显微镜重建表明,这些相互作用发生在 CP 亚基 N 端的氨基酸残基与 gRNA PS 环序列之间。PS 的碱基配对茎还通过静电促进 CP 三聚体的组装,发挥非序列特异性的作用。重要的是,PS-CP 亲和力的改变会导致结合的 PS 在 VLP 内部的不对称分布,亲和力较高的 5́ PS RNA 在一个顶点周围占据较充分的位置,而在 VLP 外壳内则减少到无 RNA 的相对顶点。这种分布表明,gRNA 的折叠调节了细胞质基因组的挤出,使含有 RNA 聚合酶结合位点的 gRNA 的弱结合 3-́ 端首先挤出。这可能发生在阳离子损失引起的 CP 壳膨胀之后,从而削弱了 CP 亚基之间的接触。这些数据首次揭示了在任何病毒中,不同的 PS 折叠倾向和 CP 亲和力是如何支持基因组在病毒组装和感染中发挥多重作用的。STNV-1 的 CP 折叠与许多其他病毒的 CP 折叠之间的高度保守性表明,基因组功能的这些方面将得到广泛共享。
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引用次数: 0
The Enigma of Transcriptional Activation Domains 转录激活域之谜。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1016/j.jmb.2024.168766

Activation domains (ADs) of eukaryotic gene activators remain enigmatic for decades as short, extremely variable sequences which often are intrinsically disordered in structure and interact with an uncertain number of targets. The general absence of specificity increasingly complicates the utilization of the widely accepted mechanism of AD function by recruitment of coactivators. The long-standing enigma at the heart of molecular biology demands a fundamental rethinking of established concepts. Here, we review the experimental evidence supporting a novel mechanistic model of gene activation, based on ADs functioning via surfactant-like near-stochastic interactions with gene promoter nucleosomes. This new model is consistent with recent information-rich experimental data obtained using high-throughput synthetic biology and bioinformatics analysis methods, including machine learning. We clarify why the conventional biochemical principle of specificity for sequence, structures, and interactions fails to explain activation domain function. This perspective provides connections to the liquid–liquid phase separation model, signifies near-stochastic interactions as fundamental for the biochemical function, and can be generalized to other cellular functions.

几十年来,真核生物基因激活子的激活结构域(ADs)一直是个谜,因为它们的序列短小、极易变化,在结构上往往是内在无序的,而且与不确定数量的靶标相互作用。由于普遍缺乏特异性,通过招募辅助激活子来发挥 AD 功能这一广为接受的机制变得越来越复杂。分子生物学核心的长期谜团要求我们从根本上重新思考既定的概念。在此,我们回顾了支持一种新型基因激活机理模型的实验证据,该模型基于 ADs 通过与基因启动子核小体的表面活性近似随机的相互作用发挥作用。这个新模型与最近利用高通量合成生物学和生物信息学分析方法(包括机器学习)获得的信息丰富的实验数据相一致。我们阐明了为什么传统的序列、结构和相互作用特异性生化原理无法解释激活结构域的功能。这一观点提供了与液-液相分离模型的联系,表明近随机相互作用是生化功能的基础,并可推广到其他细胞功能。
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引用次数: 0
Structure of Essential RNA Regulatory Elements in the West Nile Virus 3′-Terminal Stem Loop 西尼罗河病毒 3'- 末端茎环中重要 RNA 调控元件的结构。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1016/j.jmb.2024.168767

Flaviviruses, such as West Nile and Dengue Virus, pose a significant and growing threat to global health. Central to the flavivirus life cycle are highly structured 5′- and 3′-untranslated regions (UTRs), which harbor conserved cis-acting RNA elements critical for viral replication and host adaptation. Despite their essential roles, detailed molecular insights into these RNA elements have been limited. By employing nuclear magnetic resonance (NMR) spectroscopy in conjunction with SAXS experiments, we determined the three-dimensional structure of the West Nile Virus (WNV) 3′-terminal stem-loop core, a highly conserved element critical for viral genome cyclization and replication. Single nucleotide mutations at several sites within this RNA abolish the ability of the virus to replicate. These critical sites are located within a short 18-nucleotide hairpin stem, a substructure notable for its conformational flexibility, while the adjoining main stem-loop adopts a well-defined extended helix interrupted by three non-Watson-Crick pairs. This study enhances our understanding of several metastable RNA structures that play key roles in regulating the flavivirus lifecycle, and thereby also opens up potential new avenues for the development of antivirals targeting these conserved RNA structures. In particular, the structure we observe suggests that the plastic junction between the small hairpin and the tail of the longer stem-loop could provide a binding pocket for small molecules, for example potentially stabilizing the RNA in a conformation which hinders the conformational rearrangements critical for viral replication.

西尼罗河病毒和登革热病毒等黄病毒对全球健康构成了日益严重的威胁。黄病毒生命周期的核心是高度结构化的 5'- 和 3'- 非翻译区 (UTR),其中包含对病毒复制和宿主适应至关重要的保守顺式作用 RNA 元件。尽管这些 RNA 元件起着至关重要的作用,但对它们的详细分子研究却很有限。通过结合 SAXS 实验使用核磁共振(NMR)光谱,我们确定了西尼罗河病毒(WNV)3'-末端茎环核心的三维结构,这是一个高度保守的元素,对病毒基因组的环化和复制至关重要。该 RNA 中几个位点的单核苷酸突变会削弱病毒的复制能力。这些关键位点位于短短的 18 个核苷酸发夹茎中,这种子结构以其构象灵活性而著称,而相邻的主茎环则采用了明确的扩展螺旋,中间有三个非沃森-克里克对。这项研究加深了我们对在调控黄病毒生命周期中发挥关键作用的几种可转移 RNA 结构的了解,从而也为开发针对这些保守 RNA 结构的抗病毒药物开辟了潜在的新途径。特别是,我们观察到的结构表明,小发夹和较长茎环尾部之间的塑性交界处可以为小分子提供一个结合口袋,例如有可能将 RNA 稳定在一个构象中,从而阻碍病毒复制过程中至关重要的构象重排。
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引用次数: 0
RNA Polymerase II Activity Control of Gene Expression and Involvement in Disease. RNA 聚合酶 II 的活性控制基因表达并参与疾病防治。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1016/j.jmb.2024.168770
James C Kuldell, Craig D Kaplan

Gene expression is dependent on RNA Polymerase II (Pol II) activity in eukaryotes. In addition to determining the rate of RNA synthesis for all protein coding genes, Pol II serves as a platform for the recruitment of factors and regulation of co-transcriptional events, from RNA processing to chromatin modification and remodeling. The transcriptome can be shaped by changes in Pol II kinetics affecting RNA synthesis itself or because of alterations to co-transcriptional events that are responsive to or coupled with transcription. Genetic, biochemical, and structural approaches to Pol II in model organisms have revealed critical insights into how Pol II works and the types of factors that regulate it. The complexity of Pol II regulation generally increases with organismal complexity. In this review, we describe fundamental aspects of how Pol II activity can shape gene expression, discuss recent advances in how Pol II elongation is regulated on genes, and how altered Pol II function is linked to human disease and aging.

真核生物的基因表达依赖于 RNA 聚合酶 II(Pol II)的活性。Pol II 除了决定所有蛋白质编码基因的 RNA 合成速率外,还是招募因子和调控共转录事件(从 RNA 处理到染色质修饰和重塑)的平台。Pol II 动力学的变化会影响 RNA 合成本身,或改变与转录相关或耦合的共转录事件,从而改变转录组。对模式生物中 Pol II 的遗传、生化和结构研究揭示了 Pol II 的工作原理和调控因素类型。Pol II调控的复杂性通常随着生物体的复杂性而增加。在这篇综述中,我们将描述 Pol II 活性如何影响基因表达的基本方面,讨论 Pol II 延伸如何在基因上进行调控的最新进展,以及 Pol II 功能的改变如何与人类疾病和衰老有关。
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引用次数: 0
Bridging the Gap between Sequence and Structure Classifications of Proteins with AlphaFold Models 用 AlphaFold 模型弥合蛋白质序列和结构分类之间的差距。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-26 DOI: 10.1016/j.jmb.2024.168764

Classification of protein domains based on homology and structural similarity serves as a fundamental tool to gain biological insights into protein function. Recent advancements in protein structure prediction, exemplified by AlphaFold, have revolutionized the availability of protein structural data. We focus on classifying about 9000 Pfam families into ECOD (Evolutionary Classification of Domains) by using predicted AlphaFold models and the DPAM (Domain Parser for AlphaFold Models) tool. Our results offer insights into their homologous relationships and domain boundaries. More than half of these Pfam families contain DPAM domains that can be confidently assigned to the ECOD hierarchy. Most assigned domains belong to highly populated folds such as Immunoglobulin-like (IgL), Armadillo (ARM), helix-turn-helix (HTH), and Src homology 3 (SH3). A large fraction of DPAM domains, however, cannot be confidently assigned to ECOD homologous groups. These unassigned domains exhibit statistically different characteristics, including shorter average length, fewer secondary structure elements, and more abundant transmembrane segments. They could potentially define novel families remotely related to domains with known structures or novel superfamilies and folds. Manual scrutiny of a subset of these domains revealed an abundance of internal duplications and recurring structural motifs. Exploring sequence and structural features such as disulfide bond patterns, metal-binding sites, and enzyme active sites helped uncover novel structural folds as well as remote evolutionary relationships. By bridging the gap between sequence-based Pfam and structure-based ECOD domain classifications, our study contributes to a more comprehensive understanding of the protein universe by providing structural and functional insights into previously uncharacterized proteins.

根据同源性和结构相似性对蛋白质结构域进行分类是深入了解蛋白质功能的基本工具。以 AlphaFold 为代表的蛋白质结构预测技术的最新进展彻底改变了蛋白质结构数据的可用性。我们利用预测的 AlphaFold 模型和 DPAM(用于 AlphaFold 模型的领域解析器)工具,重点将约 9000 个 Pfam 家族分类为 ECOD(领域进化分类)。我们的研究结果有助于深入了解它们的同源关系和域边界。在这些 Pfam 家族中,有一半以上的 DPAM 结构域可以被可靠地分配到 ECOD 层次结构中。大多数被分配的结构域都属于高填充折叠,如免疫球蛋白样(IgL)、犰狳(ARM)、螺旋-翻转-螺旋(HTH)和 Src 同源 3(SH3)。然而,有很大一部分 DPAM 结构域无法确定归属于 ECOD 同源组。这些未归类的结构域在统计学上表现出不同的特征,包括平均长度较短、二级结构元素较少以及跨膜片段较多。它们有可能定义出与已知结构域或新型超家族和折叠结构域密切相关的新家族。对这些结构域的一个子集进行人工检查发现了大量的内部重复和重复出现的结构模式。探索序列和结构特征(如二硫键模式、金属结合位点和酶活性位点)有助于发现新的结构褶皱和远缘进化关系。通过弥合基于序列的 Pfam 和基于结构的 ECOD 结构域分类之间的差距,我们的研究提供了对以前未表征的蛋白质的结构和功能的见解,从而有助于更全面地了解蛋白质宇宙。
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引用次数: 0
Structural Basis for the Recognition of GPRC5D by Talquetamab, a Bispecific Antibody for Multiple Myeloma 多发性骨髓瘤双特异性抗体 Talquetamab 识别 GPRC5D 的结构基础。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-22 DOI: 10.1016/j.jmb.2024.168748

Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal antibody production from plasma cells. Despite advances in the treatment, many patients experience disease relapse or become refractory to treatment. G-protein-coupled receptor class C group 5 member D (GPRC5D), an orphan GPCR predominantly expressed in MM cells, is emerging as a promising target for MM immunotherapy. Talquetamab, a Food and Drug Administration-approved T-cell-directing bispecific antibody developed for treatment of MM, targets GPRC5D. Here, we elucidate the structure of GPRC5D complexed with the Fab fragment of talquetamab, using cryo-electron microscopy, providing the basis for recognition of GPRC5D by the bispecific antibody. GPRC5D forms a symmetric homodimer with the interface between transmembrane helix (TM) 4 of one protomer and TM4/5 of the other protomer. A single talquetamab Fab interacts with the GPRC5D dimer with its orientation toward the dimer interface. All six complementarity-determining regions of talquetamab engage with extracellular loops and TM3/5/7. In particular, the side-chain of an arginine residue from the antibody penetrates into a shallow pocket on the extracellular surface of GPRC5D. The structure offers insights for optimizing antibody design against GPRC5D for relapsed or refractory MM therapy.

多发性骨髓瘤(MM)是一种复杂的血液恶性肿瘤,其特点是浆细胞产生异常抗体。尽管治疗手段不断进步,但许多患者仍会复发或对治疗产生耐药性。G 蛋白偶联受体 C 类 5 组 D(GPRC5D)是一种主要在 MM 细胞中表达的孤儿 GPCR,正在成为 MM 免疫疗法的一个有希望的靶点。经美国食品药品管理局批准用于治疗 MM 的 T 细胞定向双特异性抗体 Talquetamab 靶向 GPRC5D。在这里,我们利用冷冻电镜阐明了 GPRC5D 与 Talquetamab 的 Fab 片段复合物的结构,为双特异性抗体识别 GPRC5D 提供了依据。GPRC5D 形成一个对称的同源二聚体,其中一个原体的跨膜螺旋 (TM)4 与另一个原体的 TM4/5 之间存在界面。单个 talquetamab Fab 与 GPRC5D 二聚体相互作用,其方向朝向二聚体界面。Talquetamab 的所有六个互补性决定区都与细胞外环和 TM3/5/7 相互作用。特别是,抗体中一个精氨酸残基的侧链穿透了 GPRC5D 细胞外表面的一个浅袋。该结构为优化针对 GPRC5D 的抗体设计提供了启示,可用于复发或难治性 MM 的治疗。
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引用次数: 0
Single Acetylation-mimetic Mutation in TDP-43 Nuclear Localization Signal Disrupts Importin α1/β Signaling TDP-43核定位信号中的单个乙酰化模拟突变会破坏输入蛋白α1/β的信号传导。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-22 DOI: 10.1016/j.jmb.2024.168751

Cytoplasmic aggregation of the TAR-DNA binding protein of 43 kDa (TDP-43) is the hallmark of sporadic amyotrophic lateral sclerosis (ALS). Most ALS patients with TDP-43 aggregates in neurons and glia do not have mutations in the TDP-43 gene but contain aberrantly post-translationally modified TDP-43. Here, we found that a single acetylation-mimetic mutation (K82Q) near the TDP-43 minor Nuclear Localization Signal (NLS) box, which mimics a post-translational modification identified in an ALS patient, can lead to TDP-43 mislocalization to the cytoplasm and irreversible aggregation. We demonstrate that the acetylation mimetic disrupts binding to importins, halting nuclear import and preventing importin α1/β anti-aggregation activity. We propose that perturbations near the NLS are an additional mechanism by which a cellular insult other than a genetically inherited mutation leads to TDP-43 aggregation and loss of function. Our findings are relevant to deciphering the molecular etiology of sporadic ALS.

TAR-DNA 结合蛋白 43 kDa(TDP-43)的细胞质聚集是散发性肌萎缩侧索硬化症(ALS)的特征。大多数在神经元和胶质细胞中出现 TDP-43 聚集的 ALS 患者并没有 TDP-43 基因突变,但体内含有异常翻译后修饰的 TDP-43。在这里,我们发现 TDP-43 次要核定位信号(NLS)框附近的单个乙酰化模拟突变(K82Q)可导致 TDP-43 错定位到细胞质和不可逆的聚集。我们证明,乙酰化模拟物会破坏与导入蛋白的结合,停止核导入并阻止导入蛋白α 1/ β的抗聚集活性。我们认为,NLS附近的扰动是除遗传突变以外的细胞损伤导致TDP-43聚集和功能丧失的另一种机制。我们的研究结果与破译散发性渐冻人症的分子病因有关。
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引用次数: 0
Structural Basis of Bifunctional CTP/dCTP Synthase 双功能 CTP/dCTP 合成酶的结构基础。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-20 DOI: 10.1016/j.jmb.2024.168750

The final step in the de novo synthesis of cytidine 5′-triphosphate (CTP) is catalyzed by CTP synthase (CTPS), which can form cytoophidia in all three domains of life. Recently, we have discovered that CTPS binds to ribonucleotides (NTPs) to form filaments, and have successfully resolved the structures of Drosophila melanogaster CTPS bound with NTPs. Previous biochemical studies have shown that CTPS can bind to deoxyribonucleotides (dNTPs) to produce 2′-deoxycytidine-5′-triphosphate (dCTP). However, the structural basis of CTPS binding to dNTPs is still unclear. In this study, we find that Drosophila CTPS can also form filaments with dNTPs. Using cryo-electron microscopy, we are able to resolve the structure of Drosophila melanogaster CTPS bound to dNTPs with a resolution of up to 2.7 Å. By combining these structural findings with biochemical analysis, we compare the binding and reaction characteristics of NTPs and dNTPs with CTPS. Our results indicate that the same enzyme can act bifunctionally as CTP/dCTP synthase in vitro, and provide a structural basis for these activities.

胞苷-5'-三磷酸(CTP)从头合成的最后一步是由CTP合成酶(CTPS)催化的,它可以在所有三个生命领域中形成胞丝。最近,我们发现 CTPS 可与核糖核苷酸(NTPs)结合形成丝状体,并成功解析了黑腹果蝇 CTPS 与 NTPs 结合的结构。以前的生化研究表明,CTPS 可与脱氧核苷酸(dNTPs)结合,产生 2'- 脱氧胞嘧啶-5'-三磷酸(dCTP)。然而,CTPS 与 dNTPs 结合的结构基础仍不清楚。在这项研究中,我们发现果蝇的 CTPS 也能与 dNTPs 形成丝状。我们利用低温电子显微镜解析了黑腹果蝇 CTPS 与 dNTPs 结合的结构,分辨率高达 2.7 Å。我们的研究结果表明,同一种酶可以在体外发挥 CTP/dCTP 合成酶的双重功能,并为这些活动提供了结构基础。
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引用次数: 0
The Assembly of the Inverse Autotransporter Protein YeeJ is Driven by its C-terminal β-strand 反向自转运蛋白 YeeJ 的组装是由其 C 端 β 链驱动的。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-20 DOI: 10.1016/j.jmb.2024.168749

Autotransporter proteins are bacterial outer membrane proteins that display passenger domains with various functions through a β-barrel shaped translocation domain. YeeJ is an autotransporter protein from E. coli MG1655. In contrast to most other autotransporter proteins, its passenger domain is located at the C-terminus of the translocation domain. Due to this inverted domain organization, YeeJ belongs to autotransporter proteins of type Ve. To investigate the assembly of YeeJ, the fluorescence of a heterologous mCherry passenger domain was measured to quantify its assembly. Based on AlphaFold2 models of 119 sequences similar to YeeJ, a sequence conservation logo for the β1- and the β12-strand of type Ve autotransporter proteins was generated. Then, the effect of mutations in these strands on the assembly of YeeJ were analyzed. Mutations of the N-terminal aromatic amino acid of the β1-strand did not affect the assembly of the translocation domain and the display of the passenger domain. Likewise, exchange of the β1-strand with the β3-strand did not impair the assembly of the autotransporter fusion protein. Mutation of the C-terminal aromatic amino acid of the β12-strand strongly impaired surface display of the mCherry passenger domain. This amino acid has been shown before as an essential feature of the β-signals of classical autotransporter proteins and outer membrane β-barrel proteins in general. We therefore propose that the β12-strand of YeeJ acts as its β-signal and that the assembly of the YeeJ β-barrel is driven by its C-terminal β-strand, like in most other autotransporter proteins, despite its inverted domain organization.

自转运蛋白是一种细菌外膜蛋白,通过一个β桶状转运结构域显示具有各种功能的客体结构域。YeeJ 是大肠杆菌 MG1655 的一种自转运蛋白。与大多数其他自转运蛋白不同,它的乘客结构域位于转运结构域的 C 端。由于这种倒置的结构域组织,YeeJ 属于 Ve 型自转运蛋白。为了研究 YeeJ 的组装情况,我们测量了异源 mCherry 乘客结构域的荧光,以量化其组装情况。根据与 YeeJ 相似的 119 个序列的 AlphaFold2 模型,生成了 Ve 型自体转运蛋白的 β1- 和 β12- 链的序列保护标识。然后,分析了这些链的突变对 YeeJ 组装的影响。β1-链 N 端芳香族氨基酸的突变并不影响转运结构域的组装和乘客结构域的显示。同样,用 β3 链交换 β1 链也不会影响自体转运融合蛋白的组装。β12-链 C 端芳香族氨基酸的突变强烈影响了 mCherry 乘客结构域的表面显示。该氨基酸曾被证明是经典自转运蛋白和一般外膜β管蛋白的β信号的基本特征。因此,我们认为 YeeJ 的 β12 链可作为其 β 信号,而且 YeeJ β 管的组装是由其 C 端 β 链驱动的,就像大多数其他自转运蛋白一样,尽管其结构域是倒置的。
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引用次数: 0
Conserved N-terminal Regulation of the ACA8 Calcium Pump with Two Calmodulin Binding Sites 具有两个钙调蛋白结合位点的 ACA8 钙泵 N 端保守调控。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-20 DOI: 10.1016/j.jmb.2024.168747

The autoinhibited plasma membrane calcium ATPase ACA8 from A. thaliana has an N-terminal autoinhibitory domain. Binding of calcium-loaded calmodulin at two sites located at residues 42–62 and 74–96 relieves autoinhibition of ACA8 activity.

Through activity studies and a yeast complementation assay we investigated wild-type (WT) and N-terminally truncated ACA8 constructs (Δ20, Δ30, Δ35, Δ37, Δ40, Δ74 and Δ100) to explore the role of conserved motifs in the N-terminal segment preceding the calmodulin binding sites. Furthermore, we purified WT, Δ20- and Δ100-ACA8, tested activity in vitro and performed structural studies of purified Δ20-ACA8 stabilized in a lipid nanodisc to explore the mechanism of autoinhibition.

We show that an N-terminal segment between residues 20 and 35 including conserved Phe32, upstream of the calmodulin binding sites, is important for autoinhibition and the activation by calmodulin. Cryo-EM structure determination at 3.3 Å resolution of a beryllium fluoride inhibited E2 form, and at low resolution for an E1 state combined with AlphaFold prediction provide a model for autoinhibition, consistent with the mutational studies.

拟南芥质膜钙离子ATP酶ACA8具有一个N末端的自动抑制结构域。钙载钙调蛋白与位于 42-62 和 74-96 残基的两个位点的结合可解除对 ACA8 活性的自动抑制。通过活性研究和酵母互补试验,我们研究了野生型(WT)和 N 端截短的 ACA8 构建物(Δ20、Δ30、Δ35、Δ37、Δ40、Δ74 和 Δ100),以探索钙调蛋白结合位点之前的 N 端片段中保守基团的作用。此外,我们纯化了WT、Δ20和Δ100-ACA8,在体外测试了其活性,并对稳定在脂质纳米盘中的纯化Δ20-ACA8进行了结构研究,以探索其自动抑制机制。我们的研究表明,残基 20 和 35 之间的 N 端片段(包括钙调蛋白结合位点上游的保守 Phe32)对于钙调蛋白的自动抑制和激活非常重要。以 3.3 Å 分辨率测定的氟化铍抑制 E2 状态的低温电子显微镜结构和低分辨率测定的 E1 状态的低温电子显微镜结构与 AlphaFold 预测相结合,提供了一个与突变研究相一致的自动抑制模型。
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引用次数: 0
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