Ubiquitin Modulates Liquid-Liquid Phase Separation of UBQLN2 via Disruption of Multivalent Interactions.
Ubiquitin Modulates Liquid-Liquid Phase Separation of UBQLN2 via Disruption of Multivalent Interactions.
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DOI：
10.1016/j.molcel.2018.02.004
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发表时间：
2018-03-15
期刊：
影响因子：
16
通讯作者：
Castañeda CA
中科院分区：
文献类型：
--
作者：
Dao TP;Kolaitis RM;Kim HJ;O'Donovan K;Martyniak B;Colicino E;Hehnly H;Taylor JP;Castañeda CA
在压力下，某些真核生物蛋白质和RNA组装形成无膜细胞器，称为压力颗粒。研究最充分的应激颗粒组分是RNA结合蛋白，其经历液-液相分离（LLPS），进入由内在无序的低复杂性结构域（LCD）介导的富含蛋白质的液滴。在这里，我们表明，应力颗粒包括蛋白酶体穿梭因子UBQLN 2，一个含LCD的蛋白质的结构和功能不同的RNA结合蛋白。在体外，UBQLN 2在生理条件下表现出LLPS。缺失研究将寡聚化与UBQLN 2在细胞中相分离和形成应激诱导的细胞质斑点的能力相关联。使用NMR光谱，我们映射了促进UBQLN 2寡聚化和LLPS的弱多价相互作用。UBQLN 2生物学功能所必需的泛素或多聚泛素结合消除了UBQLN 2 LLPS，从而充当液滴相和分散相之间的“开关”。我们假设，UBQLN 2 LLPS使其招聘的压力颗粒，其与泛素化底物的相互作用逆转LLPS，使客户端的穿梭压力颗粒。Ubiquilins（UBQLN）是细胞蛋白质质量控制机制的重要穿梭蛋白。在这一期的《分子细胞》中，Dao等人表明，UBQLN 2在体内与应激颗粒共定位，并在体外生理条件下经历液-液相分离。泛素结合诱导逆转UBQLN 2相分离的转变。
Under stress, certain eukaryotic proteins and RNA assemble to form membraneless organelles known as stress granules. The most well-studied stress granule components are RNA-binding proteins that undergo liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by intrinsically-disordered low-complexity domains (LCDs). Here we show that stress granules include proteasomal shuttle factor UBQLN2, a LCD-containing protein structurally and functionally distinct from RNA-binding proteins. In vitro, UBQLN2 exhibits LLPS at physiological conditions. Deletion studies correlate oligomerization with UBQLN2’s ability to phase separate and form stress-induced cytoplasmic puncta in cells. Using NMR spectroscopy, we mapped weak, multivalent interactions that promote UBQLN2 oligomerization and LLPS. Ubiquitin or polyubiquitin binding, obligatory for UBQLN2’s biological functions, eliminates UBQLN2 LLPS, thus serving as a “switch” between droplet and disperse phases. We postulate that UBQLN2 LLPS enables its recruitment to stress granules where its interactions with ubiquitinated substrates reverse LLPS to enable shuttling of clients out of stress granules. Ubiquilins (UBQLNs) are important shuttle proteins for cellular protein quality control machinery. In this issue of Molecular Cell, Dao et al. show that UBQLN2 colocalizes with stress granules in vivo and undergoes liquid-liquid phase separation at physiological conditions in vitro. Ubiquitin binding induces a transition that reverses UBQLN2 phase separation.
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影响因子：
15
作者：
Hyberts, Sven G.;Takeuchi, Koh;Wagner, Gerhard
通讯作者：
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影响因子：
3.5
作者：
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影响因子：
9.2
作者：
Cherkasov, Valeria;Hofmann, Sarah;Bukau, Bernd
通讯作者：
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影响因子：
2.6
作者：
Carvalho, Andreia F.;Pinto, Manuel P.;Azevedo, Jorge E.
通讯作者：
Azevedo, Jorge E.
DOI：
10.1074/mcp.m111.014050
发表时间：
2012-03
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Geiger T;Wehner A;Schaab C;Cox J;Mann M
通讯作者：
Mann M