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Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation. 人类 ABCD3 介导的过氧物酶体酰基-CoA 转运的结构性启示。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-03 DOI: 10.1038/s41421-024-00722-8
Yang Li, Zhi-Peng Chen, Da Xu, Liang Wang, Meng-Ting Cheng, Cong-Zhao Zhou, Yuxing Chen, Wen-Tao Hou

Human ABC transporters ABCD1-3 are all localized on the peroxisomal membrane and participate in the β-oxidation of fatty acyl-CoAs, but they differ from each other in substrate specificity. The transport of branched-chain fatty acids from cytosol to peroxisome is specifically driven by ABCD3, dysfunction of which causes severe liver diseases such as hepatosplenomegaly. Here we report two cryogenic electron microscopy (cryo-EM) structures of ABCD3 bound to phytanoyl-CoA and ATP at resolutions of 2.9 Å and 3.2 Å, respectively. A pair of phytanoyl-CoA molecules were observed in ABCD3, each binding to one transmembrane domain (TMD), which is distinct from our previously reported structure of ABCD1, where each fatty acyl-CoA molecule strongly crosslinks two TMDs. Upon ATP binding, ABCD3 exhibits a conformation that is open towards the peroxisomal matrix, leaving two extra densities corresponding to two CoA molecules deeply embedded in the translocation cavity. Structural analysis combined with substrate-stimulated ATPase activity assays indicated that the present structures might represent two states of ABCD3 in the transport cycle. These findings advance our understanding of fatty acid oxidation and the molecular pathology of related diseases.

人类 ABC 转运体 ABCD1-3 都定位于过氧物酶体膜上,参与脂肪酰基-CoAs 的β-氧化,但它们在底物特异性上有所不同。支链脂肪酸从细胞质到过氧物酶体的转运是由 ABCD3 特别驱动的,ABCD3 的功能障碍会导致严重的肝病,如肝脾肿大。在这里,我们报告了 ABCD3 与植烷酰-CoA 和 ATP 结合的两个低温电子显微镜(cryo-EM)结构,分辨率分别为 2.9 Å 和 3.2 Å。在 ABCD3 中观察到一对植物酰基-CoA 分子,每个分子与一个跨膜结构域(TMD)结合,这与我们之前报道的 ABCD1 结构不同,在 ABCD1 中,每个脂肪酰基-CoA 分子与两个跨膜结构域强烈交联。与 ATP 结合后,ABCD3 呈现出一种向过氧物酶体基质开放的构象,留下两个额外的密度,对应于深深嵌入转运腔的两个 CoA 分子。结构分析与底物刺激 ATPase 活性测定相结合表明,目前的结构可能代表了 ABCD3 在转运循环中的两种状态。这些发现加深了我们对脂肪酸氧化及相关疾病分子病理学的理解。
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引用次数: 0
Molecular mechanism of prolactin-releasing peptide recognition and signaling via its G protein-coupled receptor. 催乳素释放肽通过其 G 蛋白偶联受体识别和传递信号的分子机制。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-03 DOI: 10.1038/s41421-024-00724-6
Yang Li, Qingning Yuan, Xinheng He, Yumu Zhang, Chongzhao You, Canrong Wu, Jingru Li, H Eric Xu, Li-Hua Zhao

Prolactin-releasing peptide (PrRP) is an RF-amide neuropeptide that binds and activates its cognate G protein-coupled receptor, prolactin-releasing peptide receptor (PrRPR), also known as GPR10. PrRP and PrRPR are highly conserved across mammals and involved in regulating a range of physiological processes, including stress response, appetite regulation, pain modulation, cardiovascular function, and potentially reproductive functions. Here we present cryo-electron microscopy structures of PrRP-bound PrRPR coupled to Gq or Gi heterotrimer, unveiling distinct molecular determinants underlying the specific recognition of the ligand's C-terminal RF-amide motif. We identify a conserved polar pocket that accommodates the C-terminal amide shared by RF-amide peptides. Structural comparison with neuropeptide Y receptors reveals both similarities and differences in engaging the essential RF/RY-amide motifs. Our findings demonstrate the general mechanism governing RF-amide motif recognition by PrRPR and RF-amide peptide receptors, and provide a foundation for elucidating activation mechanisms and developing selective drugs targeting this important peptide-receptor system.

催乳素释放肽(PrRP)是一种射频酰胺神经肽,可结合并激活其同源的 G 蛋白偶联受体--催乳素释放肽受体(PrRPR),也称为 GPR10。PrRP 和 PrRPR 在哺乳动物中高度保守,参与调节一系列生理过程,包括应激反应、食欲调节、疼痛调节、心血管功能以及潜在的生殖功能。在这里,我们展示了与 Gq 或 Gi 异源三聚体偶联的 PrRP 结合的 PrRPR 的冷冻电子显微镜结构,揭示了特异性识别配体 C 端 RF-amide motif 的独特分子决定因素。我们发现了一个保守的极性口袋,可容纳 RF-amide 肽共有的 C 端酰胺。通过与神经肽 Y 受体的结构比较,我们发现了与 RF/RY-amide 重要基团结合的相似之处和不同之处。我们的研究结果证明了 PrRPR 和 RF-amide 肽受体识别 RF-amide 主题的一般机制,为阐明激活机制和开发针对这一重要肽受体系统的选择性药物奠定了基础。
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引用次数: 0
PCaseek: ultraspecific urinary tumor DNA detection using deep learning for prostate cancer diagnosis and Gleason grading. PCaseek:利用深度学习进行超特异性尿液肿瘤 DNA 检测,用于前列腺癌诊断和格里森分级。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-03 DOI: 10.1038/s41421-024-00710-y
Gaojie Li, Ye Wang, Ying Wang, Baojun Wang, Yuan Liang, Ping Wang, Yudan He, Xiaoshan Hu, Guojun Liu, Zhentao Lei, Bao Zhang, Yue Shi, Xu Gao, Xu Zhang, Weimin Ci
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引用次数: 0
Gut microbiota-derived indole-3-acetic acid suppresses high myopia progression by promoting type I collagen synthesis. 肠道微生物群衍生的吲哚-3-乙酸通过促进 I 型胶原蛋白的合成抑制高度近视的发展。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-27 DOI: 10.1038/s41421-024-00709-5
Hao Li, Yu Du, Kaiwen Cheng, Yuxi Chen, Ling Wei, Yujun Pei, Xiaoyu Wang, Lan Wang, Ye Zhang, Xiaoxin Hu, Yi Lu, Xiangjia Zhu

High myopia (HM) is a leading cause of blindness worldwide with currently no effective interventions available. A major hurdle lies in its often isolated perception as a purely ocular morbidity, disregarding potential systemic implications. Recent evidence suggests the existence of a gut-eye axis; however, the role of gut microbiota in the pathogenesis of HM remains largely unexplored. Herein, we provide a potential crosstalk among HM's gut dysbiosis, microbial metabolites, and scleral remodeling. Utilizing 16S rRNA gene sequencing, we observed an altered gut microbiota profile in HM patients with a significant reduction in probiotic abundance compared with healthy controls. Subsequent targeted metabolic profiling revealed a notable decrease in plasma levels of the gut microbiota-derived metabolite indole-3-acetic acid (3-IAA) among HM patients, which is closely associated with the reduced probiotics, both negatively correlated with HM severity. Genetic analyses determined that gut microbiota are causally associated with myopia risk. Importantly, when mice subjected to HM modeling receive fecal microbiota transplantation from healthy donors, there is an increase in 3-IAA plasma levels and simultaneous retardation of HM progression along with better maintenance of collagen type I alpha 1 (COL1A1) expression in the sclera. Furthermore, 3-IAA gavage achieves similar effects. Mechanistic investigations confirm the transcriptional activation of COL1A1 by 3-IAA via promoting the enrichment of SP1 to its promoter. Together, our findings provide novel insights into the gut microbiota-eye axis in the pathogenesis of HM and propose new strategies for HM intervention by remodeling the gut microbiota and indole supplementation.

高度近视(HM)是全球致盲的主要原因之一,目前尚无有效的干预措施。其主要障碍在于人们往往将其孤立地视为一种纯粹的眼部疾病,而忽视了其潜在的系统性影响。最近的证据表明存在肠道-眼睛轴;然而,肠道微生物群在 HM 发病机制中的作用在很大程度上仍未被探索。在此,我们提供了 HM 的肠道菌群失调、微生物代谢产物和巩膜重塑之间的潜在串联关系。通过 16S rRNA 基因测序,我们观察到 HM 患者的肠道微生物群谱发生了改变,与健康对照组相比,益生菌丰度显著降低。随后的靶向代谢谱分析显示,HM 患者的血浆中肠道微生物群衍生代谢物吲哚-3-乙酸(3-IAA)水平明显下降,这与益生菌的减少密切相关,两者均与 HM 的严重程度呈负相关。遗传分析表明,肠道微生物群与近视风险存在因果关系。重要的是,当 HM 模型小鼠接受来自健康捐赠者的粪便微生物群移植时,血浆中的 3-IAA 水平会增加,同时会延缓 HM 的发展,更好地维持巩膜中 I 型胶原蛋白α1(COL1A1)的表达。此外,灌胃 3-IAA 也能达到类似的效果。机理研究证实,3-IAA 通过促进 SP1 向其启动子富集而激活了 COL1A1 的转录。总之,我们的研究结果提供了有关 HM 发病机制中肠道微生物-眼睛轴的新见解,并提出了通过重塑肠道微生物群和补充吲哚来干预 HM 的新策略。
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引用次数: 0
Postsynaptic lncRNA Sera/Pkm2 pathway orchestrates the transition from social competition to rank by remodeling the neural ensemble in mPFC. 突触后lncRNA Sera/Pkm2通路通过重塑mPFC的神经组合,协调从社会竞争到等级的转变。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-20 DOI: 10.1038/s41421-024-00706-8
Ling-Shuang Zhu, Chuan Lai, Chao-Wen Zhou, Hui-Yang Chen, Zhi-Qiang Liu, Ziyuan Guo, Hengye Man, Hui-Yun Du, Youming Lu, Feng Hu, Zhiye Chen, Kai Shu, Ling-Qiang Zhu, Dan Liu

Individuals' continuous success in competitive interactions with conspecifics strongly affects their social hierarchy. Medial prefrontal cortex (mPFC) is the key brain region mediating both social competition and hierarchy. However, the molecular regulatory mechanisms underlying the neural ensemble in the mPFC remains unclear. Here, we demonstrate that in excitatory neurons of prelimbic cortex (PL), lncRNA Sera remodels the utilization of Pkm Exon9 and Exon10, resulting in a decrease in the Pkm1/2 ratio in highly competitive mice. By employing a tet-on/off system, we disrupt or rebuild the normal Pkm1/2 ratio by controlling the expression of Pkm2 in PL excitatory neurons. We find that long-term Pkm2 modulation induces timely competition alteration and hysteretic rank change, through phosphorylating the Ser845 site of GluA1. Together, this study uncovers a crucial role of lncRNA Sera/Pkm2 pathway in the transition of social competition to rank by remodeling neural ensemble in mPFC.

个体在与同类的竞争性互动中不断取得成功会对其社会等级产生强烈影响。内侧前额叶皮层(mPFC)是介导社会竞争和等级制度的关键脑区。然而,mPFC神经集合的分子调控机制仍不清楚。在这里,我们证明了在前边缘皮层(PL)的兴奋性神经元中,lncRNA Sera重塑了Pkm Exon9和Exon10的利用,导致高度竞争性小鼠的Pkm1/2比率下降。通过使用 tet-on/off 系统,我们控制了 PL 兴奋神经元中 Pkm2 的表达,从而破坏或重建了正常的 Pkm1/2 比率。我们发现,通过磷酸化 GluA1 的 Ser845 位点,长期的 Pkm2 调节可诱导及时的竞争改变和滞后等级变化。综上所述,本研究发现了lncRNA Sera/Pkm2通路通过重塑mPFC中的神经组合,在社会竞争向等级过渡中的关键作用。
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引用次数: 0
Structural insight into 6-OH-FAD-dependent activation of hFSP1 for ferroptosis suppression. 从结构上洞察 6-OH-FAD 依赖性激活 hFSP1 以抑制铁变态反应。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-20 DOI: 10.1038/s41421-024-00723-7
Hongying Lan, Yu Gao, Ting Hong, Zihan Chang, Zhengyang Zhao, Yanfeng Wang, Feng Wang
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引用次数: 0
Prediction of overall survival in stage II and III colon cancer through machine learning of rapidly-acquired proteomics. 通过对快速获得的蛋白质组学进行机器学习,预测 II 期和 III 期结肠癌患者的总生存期。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-13 DOI: 10.1038/s41421-024-00707-7
Kailun Xu, Xiaoyang Yin, Hui Chen, Yuhui Huang, Xi Zheng, Biting Zhou, Xue Cai, Huanhuan Gao, Miaomiao Tian, Sijun Hu, Shu Zheng, Changzheng Yuan, Yongzhan Nie, Tiannan Guo, Yingkuan Shao
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引用次数: 0
Targeting cardiac fibrosis with chimeric antigen receptor macrophages. 用嵌合抗原受体巨噬细胞靶向心脏纤维化。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-13 DOI: 10.1038/s41421-024-00718-4
Zibei Gao, Lei Yan, Jufeng Meng, Zhengkai Lu, Kaixin Ge, Zhen Jiang, Teng Feng, Haopeng Wang, Chen Liu, Juan Tang, Hui Zhang
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引用次数: 0
Structural basis for the interaction between human coronavirus HKU1 spike receptor binding domain and its receptor TMPRSS2. 人类冠状病毒 HKU1 穗状受体结合域与其受体 TMPRSS2 之间相互作用的结构基础。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-08 DOI: 10.1038/s41421-024-00717-5
Xiaopan Gao, Kaixiang Zhu, Lin Wang, Kun Shang, Lei Hua, Bo Qin, Hongtao Zhu, Wei Ding, Sheng Cui
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引用次数: 0
40 Hz light flickering facilitates the glymphatic flow via adenosine signaling in mice. 40赫兹的灯光闪烁可通过腺苷信号促进小鼠的甘液流。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-06 DOI: 10.1038/s41421-024-00701-z
Xiaoting Sun, Liliana Dias, Chenlei Peng, Ziyi Zhang, Haoting Ge, Zejun Wang, Jiayi Jin, Manli Jia, Tao Xu, Wei Guo, Wu Zheng, Yan He, Youru Wu, Xiaohong Cai, Paula Agostinho, Jia Qu, Rodrigo A Cunha, Xuzhao Zhou, Ruiliang Bai, Jiang-Fan Chen

The glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid flow in the brain parenchyma and eliminates metabolic waste. Animal and human studies have uncovered several important physiological factors regulating the glymphatic system including sleep, aquaporin-4, and hemodynamic factors. Yet, our understanding of the modulation of the glymphatic system is limited, which has hindered the development of glymphatic-based treatment for aging and neurodegenerative disorders. Here, we present the evidence from fluorescence tracing, two-photon recording, and dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced glymphatic influx and efflux independently of anesthesia and sleep, an effect attributed to increased astrocytic aquaporin-4 polarization and enhanced vasomotion. Adenosine-A2A receptor (A2AR) signaling emerged as the neurochemical underpinning of 40 Hz flickering-induced enhancement of glymphatic flow, based on increased cerebrofluid adenosine levels, the abolishment of enhanced glymphatic flow by pharmacological or genetic inactivation of equilibrative nucleotide transporters-2 or of A2AR, and by the physical and functional A2AR-aquaporin-4 interaction in astrocytes. These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders.

人们日益认识到,甘液-淋巴系统对大脑环境的平衡至关重要,因为它决定了脑实质中脑脊液的流动并清除代谢废物。动物和人体研究发现了调节甘液系统的几个重要生理因素,包括睡眠、水蒸发素-4 和血液动力学因素。然而,我们对甘液系统调控的了解还很有限,这阻碍了基于甘液系统治疗衰老和神经退行性疾病的发展。在这里,我们通过荧光追踪、双光子记录和动态对比增强磁共振成像分析证明,40 Hz 灯光闪烁可增强甘液流入和流出,而不受麻醉和睡眠的影响。腺苷-A2A受体(A2AR)信号传导是40赫兹闪烁诱导的甘油流增强的神经化学基础,其依据是脑血流中腺苷水平的增加、平衡核苷酸转运体-2或A2AR的药物或遗传失活对甘油流增强的抑制,以及星形胶质细胞中A2AR-aquaporin-4在物理和功能上的相互作用。这些研究结果表明,40 Hz 灯光闪烁是一种新型的非侵入性增强甘液流动的策略,具有缓解脑部疾病的转化潜力。
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引用次数: 0
期刊
Cell Discovery
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