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Mammalian Retromer Is an Adaptable Scaffold for Cargo Sorting from Endosomes.
Structure ( IF 4.4 ) Pub Date : 2020-02-05 , DOI: 10.1016/j.str.2020.01.009
Amy K Kendall 1 , Boyang Xie 1 , Peng Xu 2 , Jue Wang 3 , Rodger Burcham 1 , Meredith N Frazier 1 , Elad Binshtein 4 , Hui Wei 5 , Todd R Graham 2 , Terunaga Nakagawa 6 , Lauren P Jackson 7
Affiliation  

Metazoan retromer (VPS26/VPS35/VPS29) associates with sorting nexins on endosomal tubules to sort proteins to the trans-Golgi network or plasma membrane. Mechanisms of metazoan retromer assembly remain undefined. We combine single-particle cryoelectron microscopy with biophysical methods to uncover multiple oligomer structures. 2D class averages reveal mammalian heterotrimers; dimers of trimers; tetramers of trimers; and flat chains. These species are further supported by biophysical solution studies. We provide reconstructions of all species, including key sub-structures (∼5 Å resolution). Local resolution variation suggests that heterotrimers and dimers adopt multiple conformations. Our structures identify a flexible, highly conserved electrostatic dimeric interface formed by VPS35 subunits. We generate structure-based mutants to disrupt this interface in vitro. Equivalent mutations in yeast demonstrate a mild cargo-sorting defect. Our data suggest the metazoan retromer is an adaptable and plastic scaffold that accommodates interactions with different sorting nexins to sort multiple cargoes from endosomes their final destinations.

中文翻译:

哺乳动物 Retromer 是一种适应性强的支架,用于从内体中分拣货物。

后生动物逆转录酶 (VPS26/VPS35/VPS29) 与分选内体小管上的连接蛋白相关,以将蛋白质分选到跨高尔基体网络或质膜。后生动物逆转录酶组装的机制仍未明确。我们将单粒子冷冻电子显微镜与生物物理方法相结合,以揭示多种低聚物结构。二维类平均值显示哺乳动物异源三聚体;三聚体的二聚体;三聚体的四聚体;和扁链。这些物种得到生物物理解决方案研究的进一步支持。我们提供所有物种的重建,包括关键子结构(~5 Å 分辨率)。局部分辨率变化表明异三聚体和二聚体采用多种构象。我们的结构确定了由 VPS35 亚基形成的灵活、高度保守的静电二聚体界面。我们生成基于结构的突变体以在体外破坏该界面。酵母中的等效突变表现出轻微的货物分拣缺陷。我们的数据表明后生动物逆转录酶是一种适应性强的塑料支架,可适应与不同分选连接蛋白的相互作用,以将来自核内体的多种货物分选到最终目的地。
更新日期:2020-02-05
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