泛素连接酶 Ubr4 控制 podocin/MEC-2 超复合物的稳定性。,Human Molecular Genetics

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泛素连接酶 Ubr4 控制 podocin/MEC-2 超复合物的稳定性。
Human Molecular Genetics ( IF 3.1 ) Pub Date : 2016-01-19 , DOI: 10.1093/hmg/ddw016
Markus M Rinschen ₁ , Puneet Bharill ₂ , Xiongwu Wu ₃ , Priyanka Kohli ₄ , Matthäus J Reinert ₅ , Oliver Kretz ₆ , Isabel Saez ₇ , Bernhard Schermer ₈ , Martin Höhne ₈ , Malte P Bartram ₅ , Sriram Aravamudhan ₉ , Bernard R Brooks ₃ , David Vilchez ₇ , Tobias B Huber ₁₀ , Roman-Ulrich Müller ₈ , Marcus Krüger ₁₁ , Thomas Benzing ₁

Affiliation

Department II of Internal Medicine, Center for Molecular Medicine Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany,
Department II of Internal Medicine, Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany.
Laboratory of Computational Biology, National Heart, Blood, and Lung Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Department II of Internal Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and.
Department II of Internal Medicine.
Renal Division, University Hospital Freiburg, Freiburg, Germany, Neuroanatomy, University of Freiburg, Freiburg, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and.
Department II of Internal Medicine, Center for Molecular Medicine Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany.
Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany and.
Renal Division, University Hospital Freiburg, Freiburg, Germany, BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Center for Molecular Medicine Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and.

PHB结构域蛋白podocin维持肾滤过屏障，其突变是遗传性肾病综合征的重要原因。Podocin 及其秀丽隐杆线虫直系同源物 MEC-2 已成为机械敏感膜蛋白信号复合物的关键成分。足细胞蛋白存在于足细胞裂隙隔膜的特殊细胞连接处，而 MEC-2 则存在于触觉敏感所需的神经元中。在这里，我们证明泛素连接酶 Ubr4 是从培养的足细胞和天然肾小球中纯化的足蛋白相互作用组的关键成分。它与 podocin 共定位并调节其稳定性。在秀丽隐杆线虫中，这个过程是保守的。在这里，Ubr4 负责错误定位的 MEC-2 多聚体的降解。小鼠肾小球的泛素组学分析表明，podocin 在两个赖氨酸残基处泛素化。这些位点依赖于 Ubr4，并且在物种间保守。分子动力学模拟表明，一个位点 K301 的泛素化不仅会靶向 podocin/MEC-2 进行蛋白酶体降解，而且还可能影响多聚体复合物的稳定性和分解。我们认为 Ubr4 是足细胞足突蛋白质稳态的关键调节因子。

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更新日期：2019-11-01

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