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Biochemical dissection, functional characterization and regulatory cues of the assembly machinery for U snRNPs

U snRNP 组装机制的生化解剖、功能表征和调控线索

基本信息

批准号：
119111219
负责人：
Professor Dr. Utz Fischer
金额：
--
依托单位：
Lehrstuhl für Biochemie I
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/119111219?language=en
关键词：
Biochemical dissection functional characterization regulatory

项目摘要

Macromolecular complexes composed of proteins or proteins and nucleic acids perform a wide spectrum of different cellular tasks. The assembly of these macromolecular complexes often depends on trans-acting factors in vivo, as isolated subunits may aggregate or engage in wrong interactions. A paradigm for assisted assembly is the formation of the common Sm/LSm core of spliceosomal and histone-mRNA processing U snRNPs. The key assembly factors of this process are united in PRMT5- and SMN-complexes and facilitate binding of seven Sm/LSm proteins onto U snRNA. Assembly is initiated by the PRMT5-complex subunit pICln, which pre-arranges Sm/LSm proteins into spatial positions occupied in the mature U snRNP. The SMN complex then takes over these Sm/LSm units, displaces pICln and unites them with U snRNA. We have shown in the past funding period that newly synthesized Sm/LSm proteins remain bound to the ribosome even upon translation termination and that Sm/LSm guidance into the assembly pathway is dependent on pICln. Our studies uncovered an elaborate assembly line for U snRNPs in which the ribosome plays a crucial part as a quality control hub and the starting point for the chaperone-mediated assembly process. Building on these findings we are now planning to test the hypothesis that the coordinated hand-over of Sm/LSm proteins from the ribosome to the assembly machinery prevents their mis-assembly and/or aggregation and determines cellular U snRNP biogenesis. The second part of the proposal builds on our finding that several components of the SMN complex are phosphorylated and that this post-translational modification impacts on the function and sub-cellular distribution of the SMN complex. We aim to identify and further characterize signalling cues that modify the SMN complex and propose experiments that will shed light on the functional relevance of these modifications for U snRNP biogenesis and homeostasis.

由蛋白质或蛋白质和核酸组成的大分子复合物执行各种不同的细胞任务。这些大分子复合物的组装通常取决于体内的反式作用因子，因为孤立的亚基可能聚集或参与错误的相互作用。辅助组装的一个范例是剪接体和组蛋白mrna加工U snRNPs的共同Sm/LSm核心的形成。该过程的关键组装因子统一在PRMT5-和smn复合物中，并促进7种Sm/LSm蛋白与U snRNA的结合。组装由prmt5复合物亚基pICln启动，它将Sm/LSm蛋白预先排列到成熟的U snRNP中占据的空间位置。然后SMN复合体接管这些Sm/LSm单元，取代pICln并将它们与U snRNA结合。我们在过去的资助期内已经证明，即使在翻译终止后，新合成的Sm/LSm蛋白仍然与核糖体结合，并且Sm/LSm进入组装途径依赖于pICln。我们的研究揭示了一条复杂的U snRNPs组装线，其中核糖体作为质量控制中心和伴侣介导的组装过程的起点起着至关重要的作用。在这些发现的基础上，我们现在计划测试Sm/LSm蛋白从核糖体到组装机制的协调移交，以防止它们的错误组装和/或聚集，并决定细胞U snRNP生物发生的假设。该建议的第二部分建立在我们的发现之上，即SMN复合物的几个组分被磷酸化，并且这种翻译后修饰影响SMN复合物的功能和亚细胞分布。我们的目标是识别并进一步表征修饰SMN复合物的信号信号，并提出实验，以阐明这些修饰与U snRNP生物发生和稳态的功能相关性。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TOR signaling regulates liquid phase separation of the SMN complex governing snRNP biogenesis.

DOI：
10.1016/j.celrep.2021.109277
发表时间：
2021-06
期刊：
Cell reports
影响因子：
8.8
作者：
Maximilian Schilling;A. Prusty;B. Boysen;Felix S. Oppermann;Yannick Riedel;Alma Husedzinovic;H. Rasouli;A. König;Pradhipa Ramanathan;Jürgen Reymann;H. Erfle;H. Daub;U. Fischer;O. Gruss
通讯作者：
Maximilian Schilling;A. Prusty;B. Boysen;Felix S. Oppermann;Yannick Riedel;Alma Husedzinovic;H. Rasouli;A. König;Pradhipa Ramanathan;Jürgen Reymann;H. Erfle;H. Daub;U. Fischer;O. Gruss

Developmental epileptic encephalopathy with hypomyelination and brain atrophy associated with PTPN23 variants affecting the assembly of UsnRNPs