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The role of filamentous matrix molecules in shaping the architecture and emergent properties of bacterial biofilms. 丝状基质分子在塑造细菌生物膜的结构和新兴特性中的作用。
IF 4.1 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-02-21 DOI: 10.1042/BCJ20210301
Jan Böhning, Abul K Tarafder, Tanmay A M Bharat

Numerous bacteria naturally occur within spatially organised, multicellular communities called biofilms. Moreover, most bacterial infections proceed with biofilm formation, posing major challenges to human health. Within biofilms, bacterial cells are embedded in a primarily self-produced extracellular matrix, which is a defining feature of all biofilms. The biofilm matrix is a complex, viscous mixture primarily composed of polymeric substances such as polysaccharides, filamentous protein fibres, and extracellular DNA. The structured arrangement of the matrix bestows bacteria with beneficial emergent properties that are not displayed by planktonic cells, conferring protection against physical and chemical stresses, including antibiotic treatment. However, a lack of multi-scale information at the molecular level has prevented a better understanding of this matrix and its properties. Here, we review recent progress on the molecular characterisation of filamentous biofilm matrix components and their three-dimensional spatial organisation within biofilms.

许多细菌天然存在于称为生物膜的多细胞空间组织群落中。此外,大多数细菌感染都会形成生物膜,对人类健康构成重大挑战。在生物膜内,细菌细胞主要嵌在自产的细胞外基质中,这是所有生物膜的一个显著特征。生物膜基质是一种复杂的粘性混合物,主要由多糖、丝状蛋白纤维和细胞外 DNA 等高分子物质组成。基质的结构性排列赋予细菌浮游细胞所不具备的有益的突发性特性,使其能够抵御物理和化学压力,包括抗生素治疗。然而,由于缺乏分子水平的多尺度信息,人们无法更好地了解这种基质及其特性。在此,我们回顾了丝状生物膜基质成分的分子特征及其在生物膜内三维空间组织的最新进展。
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引用次数: 0
Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice. 结肠酮体生成是一个受微生物群调控的过程,它有助于血液中酮体的生成并防止小鼠患结肠炎。
IF 4.1 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230403
Kevin Bass, Sathish Sivaprakasam, Gunadharini Dharmalingam-Nandagopal, Muthusamy Thangaraju, Vadivel Ganapathy

Ketogenesis is considered to occur primarily in liver to generate ketones as an alternative energy source for non-hepatic tissues when glucose availability/utilization is impaired. 3-Hydroxy-3-methylglutaryl-CoA synthase-2 (HMGCS2) mediates the rate-limiting step in this mitochondrial pathway. Publicly available databases show marked down-regulation of HMGCS2 in colonic tissues in Crohn's disease and ulcerative colitis. This led us to investigate the expression and function of this pathway in colon and its relevance to colonic inflammation in mice. Hmgcs2 is expressed in cecum and colon. As global deletion of Hmgcs2 showed significant postnatal mortality, we used a conditional knockout mouse with enzyme deletion restricted to intestinal tract. These mice had no postnatal mortality. Fasting blood ketones were lower in these mice, indicating contribution of colonic ketogenesis to circulating ketones. There was also evidence of gut barrier breakdown and increased susceptibility to experimental colitis with associated elevated levels of IL-6, IL-1β, and TNF-α in circulation. Interestingly, many of these phenomena were mostly evident in male mice. Hmgcs2 expression in colon is controlled by colonic microbiota as evidenced from decreased expression in germ-free mice and antibiotic-treated conventional mice and from increased expression in a human colonic epithelial cell line upon treatment with aqueous extracts of cecal contents. Transcriptomic analysis of colonic epithelia from control mice and Hmgcs2-null mice indicated an essential role for colonic ketogenesis in the maintenance of optimal mitochondrial function, cholesterol homeostasis, and cell-cell tight-junction organization. These findings demonstrate a sex-dependent obligatory role for ketogenesis in protection against colonic inflammation in mice.

据认为,生酮作用主要发生在肝脏,当葡萄糖的可用性/利用率受损时,产生酮体作为非肝脏组织的替代能源。3-Hydroxy-3-methylglutaryl-CoA synthase-2(HMGCS2)介导了线粒体途径中的限速步骤。公开数据库显示,克罗恩病和溃疡性结肠炎患者结肠组织中的 HMGCS2 明显下调。这促使我们研究这条通路在结肠中的表达和功能,以及它与小鼠结肠炎症的相关性。Hmgcs2 在盲肠和结肠中表达。由于 Hmgcs2 的全面缺失会导致显著的产后死亡,我们使用了一种酶缺失仅限于肠道的条件性基因敲除小鼠。这些小鼠在出生后没有死亡。这些小鼠的空腹血酮较低,表明结肠酮体生成对循环酮体有贡献。还有证据表明,肠道屏障被破坏,对实验性结肠炎的易感性增加,循环中的 IL-6、IL-1β 和 TNF-α 水平升高。有趣的是,这些现象大多在雄性小鼠中很明显。Hmgcs2 在结肠中的表达受结肠微生物群的控制,无菌小鼠和经抗生素处理的常规小鼠中的表达量减少,以及经盲肠内容物水提取物处理的人结肠上皮细胞系中的表达量增加都证明了这一点。对对照小鼠和 Hmgcs2 基因缺失小鼠结肠上皮细胞的转录组分析表明,结肠生酮在维持线粒体功能、胆固醇平衡和细胞间紧密连接组织的最佳状态中发挥着重要作用。这些研究结果表明,在保护小鼠免受结肠炎症侵袭方面,生酮作用具有性别依赖性。
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引用次数: 0
The Parkinson's disease related mutant VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress. 与帕金森病相关的突变体 VPS35 (D620N) 会放大 LRRK2 对溶酶体内压力的反应。
IF 4.1 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230492
Katy R McCarron, Hannah Elcocks, Heather Mortiboys, Sylvie Urbé, Michael J Clague

The identification of multiple genes linked to Parkinson's disease (PD) invites the question as to how they may co-operate. We have generated isogenic cell lines that inducibly express either wild-type or a mutant form of the retromer component VPS35 (D620N), which has been linked to PD. This has enabled us to test proposed effects of this mutation in a setting where the relative expression reflects the physiological occurrence. We confirm that this mutation compromises VPS35 association with the WASH complex, but find no defect in WASH recruitment to endosomes, nor in the distribution of lysosomal receptors, cation-independent mannose-6-phosphate receptor and Sortilin. We show VPS35 (D620N) enhances the activity of the Parkinson's associated kinase LRRK2 towards RAB12 under basal conditions. Furthermore, VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress resulting in enhanced phosphorylation of RABs 10 and 12. By comparing different types of endolysosomal stresses such as the ionophore nigericin and the membranolytic agent l-leucyl-l-leucine methyl ester, we are able to dissociate phospho-RAB accumulation from membrane rupture.

与帕金森病相关的多个基因的发现,引发了这些基因如何合作的问题。我们已经生成了等基因细胞系,这些细胞系可诱导表达野生型或突变型的 retromer 成分 VPS35(D620N),后者与帕金森病有关。这使我们能够在相对表达反映生理现象的环境中测试这种突变的拟议影响。我们证实,这种突变损害了 VPS35 与 WASH 复合物的结合,但没有发现 WASH 招募到内体的缺陷,也没有发现溶酶体受体、阳离子无关的 6-磷酸甘露糖受体和 Sortilin 的分布缺陷。我们发现 VPS35 (D620N) 在基础条件下会增强帕金森氏症相关激酶 LRRK2 对 RAB12 的活性。此外,VPS35 (D620N) 还会放大 LRRK2 对内溶酶体应激的反应,导致 RABs 10 和 12 的磷酸化增强。通过比较不同类型的内溶酶体应激,如离子诱导剂尼革酶和膜溶解剂 LLOMe,我们能够将磷酸化 RAB 的积累与膜破裂区分开来。
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引用次数: 0
Beyond the tail: the consequence of context in histone post-translational modification and chromatin research. 超越尾巴:组蛋白翻译后修饰和染色质研究中的背景影响。
IF 4.1 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230342
Ellen N Weinzapfel, Karlie N Fedder-Semmes, Zu-Wen Sun, Michael-Christopher Keogh

The role of histone post-translational modifications (PTMs) in chromatin structure and genome function has been the subject of intense debate for more than 60 years. Though complex, the discourse can be summarized in two distinct - and deceptively simple - questions: What is the function of histone PTMs? And how should they be studied? Decades of research show these queries are intricately linked and far from straightforward. Here we provide a historical perspective, highlighting how the arrival of new technologies shaped discovery and insight. Despite their limitations, the tools available at each period had a profound impact on chromatin research, and provided essential clues that advanced our understanding of histone PTM function. Finally, we discuss recent advances in the application of defined nucleosome substrates, the study of multivalent chromatin interactions, and new technologies driving the next era of histone PTM research.

60 多年来,组蛋白翻译后修饰(PTM)在染色质结构和基因组功能中的作用一直是激烈争论的主题。尽管争论很复杂,但可以用两个截然不同且简单易懂的问题来概括:组蛋白 PTM 的功能是什么?应该如何研究它们?几十年的研究表明,这些问题错综复杂,远非简单明了。在此,我们从历史的角度出发,重点介绍新技术的出现如何影响了研究的发现和洞察力。尽管存在局限性,但每个时期可用的工具都对染色质研究产生了深远影响,并提供了重要线索,促进了我们对组蛋白 PTM 功能的理解。最后,我们讨论了在应用确定的核小体底物、研究多价染色质相互作用方面的最新进展,以及推动组蛋白 PTM 研究进入下一个时代的新技术。
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引用次数: 0
The role of mitochondrial RNA association for mitochondrial homeostasis in neurons 线粒体 RNA 关联对神经元线粒体平衡的作用
IF 4.1 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-02-07 DOI: 10.1042/bcj20230110
Segura, Inmaculada, Harbauer, Angelika
The sub-compartmentalization of cellular processes is especially important in highly polarized cells such as neurons, as their function rely on their complex morphology. The association of RNAs to the mitochondrial surface is a conserved feature from yeast to humans and it regulates several aspects of mitochondrial physiology and, hence, cellular functions. In neurons, mitochondria are emerging as platforms for RNA transport and local protein translation. In this review, we discuss how RNA localization to mitochondria helps to sustain mitochondrial function, and how this can support mitochondrial homeostasis, especially in the distal parts of the neuron, to support neuronal activity.
细胞过程的亚区化对于神经元等高度极化的细胞尤为重要,因为它们的功能依赖于其复杂的形态。RNA 与线粒体表面的结合是从酵母到人类的一个保守特征,它调控着线粒体生理学的多个方面,进而调控着细胞功能。在神经元中,线粒体正在成为 RNA 运输和局部蛋白质翻译的平台。在这篇综述中,我们将讨论 RNA 在线粒体上的定位如何有助于维持线粒体的功能,以及这如何支持线粒体的平衡,尤其是在神经元的远端部分,以支持神经元的活动。
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引用次数: 0
A highly conserved ligand-binding site for AccA transporters of antibiotic and quorum-sensing regulator in Agrobacterium leads to a different specificity. 在农杆菌中,抗生素和群体感应调节剂的AccA转运体的高度保守的配体结合位点导致了不同的特异性。
IF 4.1 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-25 DOI: 10.1042/BCJ20230273
Solange Moréra, Armelle Vigouroux, Magali Aumont-Nicaise, Mohammed Ahmar, Thibault Meyer, Abbas El Sahili, Grégory Deicsics, Almudena González-Mula, Sizhe Li, Jeanne Doré, Serena Sirigu, Pierre Legrand, Camille Penot, François André, Denis Faure, Laurent Soulère, Yves Queneau, Ludovic Vial

Plants genetically modified by the pathogenic Agrobacterium strain C58 synthesize agrocinopines A and B, whereas those modified by the pathogenic strain Bo542 produce agrocinopines C and D. The four agrocinopines (A, B, C and D) serve as nutrients by agrobacteria and signaling molecule for the dissemination of virulence genes. They share the uncommon pyranose-2-phosphate motif, represented by the l-arabinopyranose moiety in agrocinopines A/B and the d-glucopyranose moiety in agrocinopines C/D, also found in the antibiotic agrocin 84. They are imported into agrobacterial cytoplasm via the Acc transport system, including the solute-binding protein AccA coupled to an ABC transporter. We have previously shown that unexpectedly, AccA from strain C58 (AccAC58) recognizes the pyranose-2-phosphate motif present in all four agrocinopines and agrocin 84, meaning that strain C58 is able to import agrocinopines C/D, originating from the competitor strain Bo542. Here, using agrocinopine derivatives and combining crystallography, affinity and stability measurements, modeling, molecular dynamics, in vitro and vivo assays, we show that AccABo542 and AccAC58 behave differently despite 75% sequence identity and a nearly identical ligand binding site. Indeed, strain Bo542 imports only compounds containing the d-glucopyranose-2-phosphate moiety, and with a lower affinity compared with strain C58. This difference in import efficiency makes C58 more competitive than Bo542 in culture media. We can now explain why Agrobacterium/Allorhizobium vitis strain S4 is insensitive to agrocin 84, although its genome contains a conserved Acc transport system. Overall, our work highlights AccA proteins as a case study, for which stability and dynamics drive specificity.

经致病性农杆菌菌株C58基因修饰的植物合成agrocinopines A和B,而经致病性菌株Bo542基因修饰的植物产生agrocinopines C和D。这四种agrocinopines (A、B、C和D)通过农杆菌和信号分子作为营养物质传播毒力基因。它们共享罕见的吡喃糖-2-磷酸基序,以agrocinopines A/B中的L-arabinopyranose片段和agrocinopines C/D中的D-glucopyranose片段为代表,也在抗生素agrocin 84中发现。它们通过Acc转运系统(包括与ABC转运蛋白偶联的溶质结合蛋白AccA)进入农杆菌细胞质。我们之前意外地发现,来自菌株C58 (AccAC58)的AccA识别了所有四种agrocinopines和agrocin84中存在的pyranose-2-phosphate基序,这意味着菌株C58能够进口源自竞争菌株Bo542的agrocinopines C/D。在这里,我们使用农用罂粟碱衍生物,结合晶体学、亲和力和稳定性测量、建模、分子动力学、体外和体内实验,我们发现AccABo542和AccAC58在75%的序列相同和几乎相同的配体结合位点的情况下表现不同。事实上,菌株Bo542只输入含有d -葡萄糖吡喃糖-2-磷酸片段的化合物,与菌株C58相比,亲和力较低。这种进口效率的差异使得C58在培养基上比Bo542更具竞争力。我们现在可以解释为什么农杆菌/葡萄异根菌菌株S4对agrocin 84不敏感,尽管它的基因组包含一个保守的Acc转运系统。总的来说,我们的工作突出了AccA蛋白作为一个案例研究,其稳定性和动力学驱动特异性。
{"title":"A highly conserved ligand-binding site for AccA transporters of antibiotic and quorum-sensing regulator in Agrobacterium leads to a different specificity.","authors":"Solange Moréra, Armelle Vigouroux, Magali Aumont-Nicaise, Mohammed Ahmar, Thibault Meyer, Abbas El Sahili, Grégory Deicsics, Almudena González-Mula, Sizhe Li, Jeanne Doré, Serena Sirigu, Pierre Legrand, Camille Penot, François André, Denis Faure, Laurent Soulère, Yves Queneau, Ludovic Vial","doi":"10.1042/BCJ20230273","DOIUrl":"10.1042/BCJ20230273","url":null,"abstract":"<p><p>Plants genetically modified by the pathogenic Agrobacterium strain C58 synthesize agrocinopines A and B, whereas those modified by the pathogenic strain Bo542 produce agrocinopines C and D. The four agrocinopines (A, B, C and D) serve as nutrients by agrobacteria and signaling molecule for the dissemination of virulence genes. They share the uncommon pyranose-2-phosphate motif, represented by the l-arabinopyranose moiety in agrocinopines A/B and the d-glucopyranose moiety in agrocinopines C/D, also found in the antibiotic agrocin 84. They are imported into agrobacterial cytoplasm via the Acc transport system, including the solute-binding protein AccA coupled to an ABC transporter. We have previously shown that unexpectedly, AccA from strain C58 (AccAC58) recognizes the pyranose-2-phosphate motif present in all four agrocinopines and agrocin 84, meaning that strain C58 is able to import agrocinopines C/D, originating from the competitor strain Bo542. Here, using agrocinopine derivatives and combining crystallography, affinity and stability measurements, modeling, molecular dynamics, in vitro and vivo assays, we show that AccABo542 and AccAC58 behave differently despite 75% sequence identity and a nearly identical ligand binding site. Indeed, strain Bo542 imports only compounds containing the d-glucopyranose-2-phosphate moiety, and with a lower affinity compared with strain C58. This difference in import efficiency makes C58 more competitive than Bo542 in culture media. We can now explain why Agrobacterium/Allorhizobium vitis strain S4 is insensitive to agrocin 84, although its genome contains a conserved Acc transport system. Overall, our work highlights AccA proteins as a case study, for which stability and dynamics drive specificity.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"93-117"},"PeriodicalIF":4.1,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138497730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 mTORC2 signaling network: targets and cross-talks. mTORC2 信号网络:目标和交叉联系。
IF 4.1 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-25 DOI: 10.1042/BCJ20220325
Aparna Ragupathi, Christian Kim, Estela Jacinto

The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.

雷帕霉素的机制靶标(mTOR)控制着细胞的新陈代谢,以应对生长信号和应激刺激。mTOR 的细胞功能由两个不同的蛋白复合物介导,即 mTOR 复合物 1(mTORC1)和 mTORC2。雷帕霉素及其类似物目前在临床上用于治疗多种疾病,并在阐明其直接靶标 mTORC1 的功能方面发挥了重要作用。尽管缺乏特异性的 mTORC2 抑制剂,但通过基因研究破坏 mTORC2 的表达,可以揭示这一更难以捉摸的 mTOR 复合物的功能。与 mTORC1 响应生长信号一样,mTORC2 也会被合成代谢信号激活,但也会被压力触发。人们对营养限制等应激条件如何调节 mTORC2 的激活以实现代谢重编程并确保细胞存活仍知之甚少。mTORC2的下游效应因子种类繁多,但表征最明确的mTORC2底物包括AGC蛋白激酶家族成员Akt、PKC和SGK。在此,我们回顾了 mTORC2 是如何受细胞刺激调控的,包括复杂成分的区隔和调节是如何影响 mTORC2 信号传导的。我们详细阐述了其底物(尤其是 AGC 激酶)的磷酸化如何介导其在生长、增殖、存活和分化中的各种功能。我们还讨论了与 mTORC2 交叉作用的其他信号和代谢成分,以及这些信号的细胞输出。最后,我们将探讨如何更有效地针对 mTORC2 通路治疗 mTOR 信号失调的疾病。
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引用次数: 0
The role of phosphorylation in calmodulin-mediated gating of human AQP0. 磷酸化在钙调素介导的人AQP0门控中的作用。
IF 4.1 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-10 DOI: 10.1042/BCJ20230158
Stefan Kreida, Jennifer Virginia Roche, Julie Winkel Missel, Tamim Al-Jubair, Carl Johan Hagströmer, Veronika Wittenbecher, Sara Linse, Pontus Gourdon, Susanna Törnroth-Horsefield

Aquaporin-0 (AQP0) is the main water channel in the mammalian lens and is involved in accommodation and maintaining lens transparency. AQP0 binds the Ca2+-sensing protein calmodulin (CaM) and this interaction is believed to gate its water permeability by closing the water-conducting pore. Here, we express recombinant and functional human AQP0 in Pichia pastoris and investigate how phosphorylation affects the interaction with CaM in vitro as well as the CaM-dependent water permeability of AQP0 in proteoliposomes. Using microscale thermophoresis and surface plasmon resonance technology we show that the introduction of the single phospho-mimicking mutations S229D and S235D in AQP0 reduces CaM binding. In contrast, CaM interacts with S231D with similar affinity as wild type, but in a different manner. Permeability studies of wild-type AQP0 showed that the water conductance was significantly reduced by CaM in a Ca2+-dependent manner, whereas AQP0 S229D, S231D and S235D were all locked in an open state, insensitive to CaM. We propose a model in which phosphorylation of AQP0 control CaM-mediated gating in two different ways (1) phosphorylation of S229 or S235 abolishes binding (the pore remains open) and (2) phosphorylation of S231 results in CaM binding without causing pore closure, the functional role of which remains to be elucidated. Our results suggest that site-dependent phosphorylation of AQP0 dynamically controls its CaM-mediated gating. Since the level of phosphorylation increases towards the lens inner cortex, AQP0 may become insensitive to CaM-dependent gating along this axis.

水通道蛋白-0 (AQP0)是哺乳动物晶状体中的主要通道,参与调节和维持晶状体的透明度。AQP0结合Ca2+感应蛋白钙调蛋白(CaM),这种相互作用被认为通过关闭导水孔来控制其水渗透性。本研究在帕斯德酵母中表达重组的功能性人类AQP0,并研究磷酸化如何影响体外与CaM的相互作用以及AQP0在蛋白脂质体中依赖CaM的透水性。利用微尺度热泳(MST)和表面等离子体共振(SPR)技术,我们发现在AQP0中引入单磷酸模拟突变S229D和S235D减少了cam结合。相比之下,CaM与S231D的相互作用与野生型具有相似的亲和力,但方式不同。对野生型AQP0的渗透性研究表明,CaM以Ca2+依赖的方式显著降低了AQP0的水电导,而AQP0 S229D、S231D和S235D均锁定在开放状态,对CaM不敏感。我们提出了一个模型,其中AQP0的磷酸化以两种不同的方式控制cam介导的门控(1)S229或S235的磷酸化消除了结合(孔保持开放),(2)S231的磷酸化导致cam结合而不导致孔关闭,其功能作用仍有待阐明。我们的研究结果表明,AQP0的位点依赖性磷酸化动态控制其cam介导的门控。由于磷酸化水平向晶状体内皮层方向增加,AQP0可能对沿该轴的cam依赖性门控变得不敏感。
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引用次数: 0
Proximity labelling reveals effects of disease-causing mutation on the DNAJC5/cysteine string protein α interactome. 近距离标记揭示了致病突变对DNAJC5/半胱氨酸串联蛋白α相互作用组的影响。
IF 4.1 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-09 DOI: 10.1042/BCJ20230319
Eleanor Barker, Amy Milburn, Nordine Helassa, Dean Hammond, Natalia Sanchez-Soriano, Alan Morgan, Jeff Barclay

Cysteine string protein α (CSPα), also known as DNAJC5, is a member of the DnaJ/Hsp40 family of co-chaperones. The name derives from a cysteine-rich domain, palmitoylation of which enables localization to intracellular membranes, notably neuronal synaptic vesicles. Mutations in the DNAJC5 gene that encodes CSPα cause autosomal dominant, adult-onset neuronal ceroid lipofuscinosis (ANCL), a rare neurodegenerative disease. As null mutations in CSP-encoding genes in flies, worms and mice similarly result in neurodegeneration, CSP is evidently an evolutionarily conserved neuroprotective protein. However, the client proteins that CSP chaperones to prevent neurodegeneration remain unclear. Traditional methods for identifying protein-protein interactions such as yeast 2-hybrid and affinity purification approaches are poorly suited to CSP, due to its requirement for membrane anchoring and its tendency to aggregate after cell lysis. Therefore, we employed proximity labelling, which enables identification of interacting proteins in situ in living cells via biotinylation. Neuroendocrine PC12 cell lines stably expressing wild type or L115R ANCL mutant CSP constructs fused to miniTurbo were generated; then the biotinylated proteomes were analysed by liquid chromatographymass spectrometry (LCMS) and validated by western blotting. This confirmed several known CSP-interacting proteins, such as Hsc70 and SNAP-25, but also revealed novel binding proteins, including STXBP1/Munc18-1. Interestingly, some protein interactions (such as Hsc70) were unaffected by the L115R mutation, whereas others (including SNAP-25 and STXBP1/Munc18-1) were inhibited. These results define the CSP interactome in a neuronal model cell line and reveal interactions that are affected by ANCL mutation and hence may contribute to the neurodegeneration seen in patients.

半胱氨酸串联蛋白α(CSPα)又称 DNAJC5,是 DnaJ/Hsp40 协同伴侣蛋白家族的成员。其名称源于一个富含半胱氨酸的结构域,该结构域的棕榈酰化作用可使其定位到细胞内膜,特别是神经元突触囊泡。编码 CSPα 的 DNAJC5 基因发生突变会导致常染色体显性、成人发病型神经细胞类脂膜炎(ANCL),这是一种罕见的神经退行性疾病。在苍蝇、蠕虫和小鼠中,CSP编码基因的无效突变同样会导致神经退行性病变,因此CSP显然是一种进化保守的神经保护蛋白。然而,目前仍不清楚 CSP 可通过与哪些客户蛋白结合来防止神经退行性变。传统的蛋白质-蛋白质相互作用鉴定方法,如酵母双杂交和亲和纯化方法,都不太适合 CSP,因为它需要膜锚定,而且细胞裂解后容易聚集。因此,我们采用了近距离标记法,通过生物素化在活细胞中原位鉴定相互作用的蛋白质。我们生成了稳定表达与 miniTurbo 融合的野生型或 L115R ANCL 突变型 CSP 构建物的神经内分泌 PC12 细胞系;然后用液相色谱-质谱联用仪(LCMS)分析了生物素化的蛋白质组,并用 Western 印迹法进行了验证。这证实了几种已知的 CSP 相互作用蛋白,如 Hsc70 和 SNAP-25,但也发现了新的结合蛋白,包括 STXBP1/Munc18-1。有趣的是,一些蛋白质的相互作用(如 Hsc70)不受 L115R 突变的影响,而另一些(包括 SNAP-25 和 STXBP1/Munc18-1)则受到抑制。这些结果确定了神经元模型细胞系中的CSP相互作用组,揭示了受ANCL突变影响的相互作用,因此可能导致患者的神经退行性变。
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引用次数: 0
The consequence of ATP synthase dimer angle on mitochondrial morphology studied by cryo-electron tomography. 利用低温电子断层扫描技术研究 ATP 合酶二聚体角度对线粒体形态的影响。
IF 4.1 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-02 DOI: 10.1042/BCJ20230450
Emma Buzzard, Mathew McLaren, Piotr Bragoszewski, Andrea Brancaccio, Holly Ford, Bertram Daum, Patricia Kuwabara, Ian Collinson, Vicki Gold

Mitochondrial ATP synthases form rows of dimers, which induce membrane curvature to give cristae their characteristic lamellar or tubular morphology. The angle formed between the central stalks of ATP synthase dimers varies between species. Using cryo-electron tomography and sub-tomogram averaging, we determined the structure of the ATP synthase dimer from the nematode worm C. elegans and show that the dimer angle differs from previously determined structures. The consequences of this species-specific difference at the dimer interface were investigated by comparing C. elegans and S. cerevisiae mitochondrial morphology. We reveal that C. elegans has a larger ATP synthase dimer angle with more lamellar (flatter) cristae when compared to yeast. The underlying cause of this difference was investigated by generating an atomic model of the C. elegans ATP synthase dimer by homology modelling. A comparison of our C. elegans model to an existing S. cerevisiae structure reveals the presence of extensions and rearrangements in C. elegans subunits associated with maintaining the dimer interface. We speculate that increasing dimer angles could provide an advantage for species that inhabit variable-oxygen environments by forming flatter more energetically efficient cristae.

线粒体 ATP 合成酶形成成排的二聚体,这些二聚体促使膜弯曲,从而使嵴呈现出特有的片状或管状形态。ATP 合成酶二聚体中心柄之间形成的角度因物种而异。利用低温电子断层扫描和子图平均法,我们确定了线虫C. elegans的ATP合成酶二聚体的结构,并表明二聚体的角度与之前确定的结构不同。通过比较线虫和麦角虫的线粒体形态,我们研究了二聚体界面上这种物种特异性差异的后果。我们发现,与酵母相比,秀丽隐杆线粒体的 ATP 合酶二聚体角度更大,嵴的片状(扁平)更多。我们通过同源建模生成了优雅子 ATP 合酶二聚体的原子模型,从而研究了造成这种差异的根本原因。将我们的秀丽隐杆线虫模型与现有的 S. cerevisiae 结构进行比较后发现,秀丽隐杆线虫亚基中存在与维持二聚体界面相关的延伸和重排。我们推测,增加二聚体角度可以形成更扁平、能量效率更高的嵴,从而为栖息在变氧环境中的物种提供优势。
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