更新于：2024-05-01

MDN1

midasin AAA ATPase 1

更新于：2024-05-01

基本信息

别名

Dynein-related AAA-ATPase MDN1、KIAA0301、MDN1

+ [4]

简介

Nuclear chaperone required for maturation and nuclear export of pre-60S ribosome subunits (PubMed:27814492). Functions at successive maturation steps to remove ribosomal factors at critical transition points, first driving the exit of early pre-60S particles from the nucleolus and then driving late pre-60S particles from the nucleus (By similarity). At an early stage in 60S maturation, mediates the dissociation of the PeBoW complex (PES1-BOP1-WDR12) from early pre-60S particles, rendering them competent for export from the nucleolus to the nucleoplasm (By similarity). Subsequently recruited to the nucleoplasmic particles through interaction with SUMO-conjugated PELP1 complex (PubMed:27814492). This binding is only possible if the 5S RNP at the central protuberance has undergone the rotation to complete its maturation (By similarity).

关联

100 项与 MDN1 相关的临床结果

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100 项与 MDN1 相关的转化医学

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0 项与 MDN1 相关的专利（医药）

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项与 MDN1 相关的文献（医药）

2023-11-08·Laboratory investigation; a journal of technical methods and pathology

Omic Studies on In vitro Cystinosis Model: siRNA-mediated CTNS gene silencing in HK-2 cells.

Article

作者: İpek Baysal ; Samiye Yabanoglu-Ciftci ; Emirhan Nemutlu ; Cemil Can Eylem ; Elif Damla Gök-Topak ; Kezban Ulubayram ; Sedef Kır ; Bora Gulhan ; Gülberk Uçar ; Fatih Ozaltin ; Rezan Topaloglu

Cystinosis is an autosomal recessive disease caused by mutations in the CTNS gene encoding a protein called cystinosine, which is a lysosomal cystine transporter. Disease causing mutations lead accumulation of cystine crystals in the lysosomes and thereby causing dysfunction of vital organs. Determination of the increased leukocyte cystine level is one of the most used methods for diagnosis. However, this method is expensive, difficult to perform, and may yield different results in different laboratories. In this study, a disease model was created with CTNS gene-silenced HK2 cells, which can mimic cystinosis in cell culture, and multi-omics methods (i.e., proteomics, metabolomics and fluxomics) were implemented at this cell culture to investigate new biomarkers for the diagnosis. CTNS-silenced cell line exhibited distinct metabolic profiles compared to the control cell line. Pathway analysis highlighted significant alterations in various metabolic pathways, including alanine, aspartate, and glutamate metabolism, glutathione metabolism, aminoacyl-tRNA biosynthesis, arginine and proline metabolism, beta-alanine metabolism, ascorbate and aldarate metabolism, and histidine metabolism upon CTNS silencing. Fluxomics analysis revealed increased cycle rates of Krebs cycle intermediates such as fumarate, malate, and citrate, accompanied by enhanced activation of inorganic phosphate and ATP production. Furthermore, proteomic analysis unveiled differential expression levels of key proteins involved in crucial cellular processes. Notably, peptidyl-prolyl cis-trans isomerase A, translation elongation factor 1-beta (EF-1beta), and 60S acidic ribosomal protein decreased in CTNS-silenced cells. Additionally, levels of P0 and tubulin alpha-1A chain reduced, while levels of 40S ribosomal protein S8 and Midasin increased. Overall, our study, through the utilization of an in vitro cystinosis model and comprehensive multi-omics approach, led to the way toward the identification of potential new biomarkers while offering valuable insights into the pathogenesis of cystinosis.

2023-05-29·Nucleic acids research

eEF2 diphthamide modification restrains spurious frameshifting to maintain translational fidelity.

Article

作者: Byung-Sik Shin ; Ivaylo P Ivanov ; Joo-Ran Kim ; Chune Cao ; Terri G Kinzy ; Thomas E Dever

Diphthamide (DPH), a conserved amino acid modification on eukaryotic translation elongation factor eEF2, is synthesized via a complex, multi-enzyme pathway. While DPH is non-essential for cell viability and its function has not been resolved, diphtheria and other bacterial toxins ADP-ribosylate DPH to inhibit translation. Characterizing Saccharomyces cerevisiae mutants that lack DPH or show synthetic growth defects in the absence of DPH, we show that loss of DPH increases resistance to the fungal translation inhibitor sordarin and increases -1 ribosomal frameshifting at non-programmed sites during normal translation elongation and at viral programmed frameshifting sites. Ribosome profiling of yeast and mammalian cells lacking DPH reveals increased ribosomal drop-off during elongation, and removal of out-of-frame stop codons restores ribosomal processivity on the ultralong yeast MDN1 mRNA. Finally, we show that ADP-ribosylation of DPH impairs the productive binding of eEF2 to elongating ribosomes. Our results reveal that loss of DPH impairs the fidelity of translocation during translation elongation resulting in increased rates of ribosomal frameshifting throughout elongation and leading to premature termination at out-of-frame stop codons. We propose that the costly, yet non-essential, DPH modification has been conserved through evolution to maintain translational fidelity despite being a target for inactivation by bacterial toxins.

2023-03-17·eLife

Concurrent remodeling of nucleolar 60S subunit precursors by the Rea1 ATPase and Spb4 RNA helicase.

Article

作者: Valentin Mitterer ; Matthias Thoms ; Robert Buschauer ; Otto Berninghausen ; Ed Hurt ; Roland Beckmann

Biogenesis intermediates of nucleolar ribosomal 60S precursor particles undergo a number of structural maturation steps before they transit to the nucleoplasm and are finally exported into the cytoplasm. The AAA⁺-ATPase Rea1 participates in the nucleolar exit by releasing the Ytm1-Erb1 heterodimer from the evolving pre-60S particle. Here, we show that the DEAD-box RNA helicase Spb4 with its interacting partner Rrp17 is further integrated into this maturation event. Spb4 binds to a specific class of late nucleolar pre-60S intermediates, whose cryo-EM structure revealed how its helicase activity facilitates melting and restructuring of 25S rRNA helices H62 and H63/H63a prior to Ytm1-Erb1 release. In vitro maturation of such Spb4-enriched pre-60S particles, incubated with purified Rea1 and its associated pentameric Rix1-complex in the presence of ATP, combined with cryo-EM analysis depicted the details of the Rea1-dependent large-scale pre-ribosomal remodelling. Our structural insights unveil how the Rea1 ATPase and Spb4 helicase remodel late nucleolar pre-60S particles by rRNA restructuring and dismantling of a network of several ribosomal assembly factors.

项与 MDN1 相关的新闻（医药）

2024-02-06

·生物探索

Nat Commun | 复旦大学丁琛/陈治宇通过血浆蛋白质谱揭示结直肠癌诊断和西妥昔单抗治疗反应的生物标志物多样性

引言西妥昔单抗治疗是结直肠癌（CRC）的主要治疗方法，但耐药性限制了其有效性。2024年2月1日，复旦大学丁琛及陈治宇共同通讯在Nature Communications (IF 16.6)发表题为“Longitudinal plasma proteome profiling reveals the diversity of biomarkers for diagnosis and cetuximab therapy response of colorectal cancer”的研究论文，该研究对来自147名接受西妥昔单抗多疗程治疗的CRC患者（CRC）和90名健康对照（HC）的641份血浆样本进行了纵向和深度蛋白质组学分析。COL12A1、THBS2、S100A8和S100A9作为潜在蛋白进行筛选，以在血浆和组织验证队列中区分CRC和HC。该研究确定了潜在的生物标志物（RRAS2、MMP8、FBLN1、RPTOR 和 IMPDH2）用于初始疗效预测。在纵向研究中，确定了具有不同波动的两个集群，并构建了高精度的模型来预测纵向应答，并在独立队列中进一步验证。该研究揭示了不同生物标志物在肿瘤诊断、西妥昔单抗首疗程和多疗程治疗的初始和纵向疗效预测方面的异质性，可能最终有助于CRC的监测和干预策略。结直肠癌（CRC）是全球第三大常见癌症。对于结直肠癌患者，筛查已被证明可以降低平均风险女性和平均风险男性的癌症死亡率。然而，疾病进展缓慢且无症状，使得早期诊断具有挑战性，这严重降低了及时发现和干预疾病的机会。因此，当务之急是探索潜在的生物标志物，以区分CRC患者和健康对照者，从而提高无创准确的诊断策略。大约一半的结直肠癌患者死于转移性疾病。目前不可切除结直肠癌患者的一线治疗标准是化疗联合单克隆抗体（mAb）。经过20多年的转化和临床研究，EGFR家族及其细胞内信号通路仍然是CRC靶向分子治疗的关键。表皮生长因子受体(EGFR, HER1)是一种具有酪氨酸激酶酶活性的细胞膜生长因子受体家族中的生长因子受体。西妥昔单抗是一种针对EGFR的嵌合单克隆抗体，通过阻断配体结合区、阻断配体诱导的EGFR酪氨酸激酶激活和随后导致癌细胞增殖的信号转导事件，以高亲和力特异性结合 EGFR。一项随机试验（CO.17）显示，在对晚期化疗无反应的CRC患者中，西妥昔单抗比单独使用最佳支持治疗改善了总生存期和无进展生存期，并更好地保留了生活质量。虽然约85%的CRC患者表达EGFR，但西妥昔单抗耐药的情况常见，在第一次评估时，超过50%的接受治疗患者已发生疾病进展。因此，有必要找到西妥昔单抗首次治疗反应的潜在预测性生物标志物。KRAS激活突变的存在被发现是CRC抗EGFR治疗的第一个预测性阴性生物标志物。已经研究了一系列可能有助于预测对EGFR抑制剂反应的潜在生物标志物。此外，获得性耐药性不可避免地出现，所有患者都发生疾病进展，这限制了药物的临床疗效。获得性耐药性的出现使患者无法长期受益；然而，获得性耐药性的早期预警仍不清楚。因此，在CRC患者的每个治疗过程中进行动态抽样是必要的，并有助于很好地理解西妥昔单抗治疗期间与治疗反应相关的动态轨迹。基于质谱（MS）的血浆蛋白质组学已成功应用于疾病诊断和疾病中蛋白质变化轨迹的表征，表明它是在这种易于获取的血浆样品中发现生物标志物的最佳技术。在该研究中，收集了来自116例接受西妥昔单抗连续多个疗程治疗的结直肠癌患者(CRC)和66名健康对照(HC)的540份血浆样本(血浆发现队列)，来自31例CRC和24例HC的101份血浆样本(血浆验证队列)，以及来自31例治疗初期CRC的31份肿瘤组织样本和27份配对的癌旁组织(NAT)。研究对血浆蛋白质组进行了无偏倚的全面分析，以寻找CRC诊断和西妥昔单抗治疗反应的生物标志物。首先对接受过治疗的CRC患者和健康对照者的蛋白质组谱进行了比较蛋白质组学分析。结果显示，治疗前的CRC患者具有细胞外基质组织（ECM）的特征。研究鉴定出主要参与ECM通路的COL12A1、THBS2、S100A8和S100A9蛋白，可作为有效的生物标志物，在独立的组织和血浆验证队列中得到了进一步验证。此外，研究者还在更广泛的CRC患者人群中验证了这4种蛋白的预测效果，但不限于RAS野生型CRC患者或转移性CRC患者。该研究还探索了4种蛋白能很好地区别CRCs和HCs，但不能区分其他癌症和非恶性疾病的患者，表明这4种蛋白对CRC诊断具有相对特异性。然后，研究对治疗前结直肠癌患者的蛋白质组谱进行了共识聚类分析，确定了3种具有不同生物过程特征的蛋白质组亚型，并与不同的治疗反应相关。RRAS2、MMP8、FBLN1、RPTOR和IMPDH2等通路关键调控因子可作为西妥昔单抗首次治疗反应预测的生物标志物，用于区分敏感患者和非敏感患者，并在独立的组织和血浆验证队列中进行了验证。CRC队列和健康对照的血浆蛋白质组学分析总结（Credit: Nature Communications）此外，研究分析了一个纵向队列，以确定与西妥昔单抗治疗反应相关的具有动态变化的蛋白质。最后，采用logistic回归策略构建由IDH3G、MDN1、KLC4、MYL9、SBF1和HTRA3组成的预测模型，对多疗程西妥昔单抗治疗的反应预测精度较高。该预测模型的稳健性在独立血浆队列中得到了进一步验证。该研究提供了西妥昔单抗治疗过程中患者血浆蛋白的动态变化，并确定了用于肿瘤诊断、初始疗效预测和纵向疗效预测的潜在生物标志物，揭示了这些不同生物标志物在结直肠癌临床管理中的异质性。原文链接https://doi.org/10.1038/s41467-024-44911-1责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

临床研究