A model for Scc2p stimulation of cohesin's ATPase and its inhibition by acetylation of Smc3p.
A model for Scc2p stimulation of cohesin's ATPase and its inhibition by acetylation of Smc3p.
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DOI：
10.1101/gad.350278.122
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发表时间：
2023-04-01
影响因子：
10.5
通讯作者：
Koshland, Douglas
中科院分区：
文献类型：
--
作者：
Boardman, Kevin;Xiang, Siheng;Chatterjee, Fiona;Mbonu, Udochi;Guacci, Vincent;Koshland, Douglas
在这项研究中，Boardman等人。描述辅助因子Scc2p和粘附素成分Smc1p和Smc3p之间的相互作用如何对复合体的ATPase活性至关重要。他们提出了一个模型，在该模型中，Scc2p-Smc1p结合通过将ATP转移到活性部位来刺激Smc3p的ATPase，而Smc3p乙酰化干扰Scc2p-Smc1p接口并抑制ATPase活性。进化上保守的粘附素复合体介导姐妹染色单体凝聚，促进有丝分裂染色体凝聚、DNA修复和转录调节。这些生物学功能需要粘附素的两个ATPase，由Smc1p和Smc3p亚基组成。粘附素的ATPase活性受Scc2p辅助因子的刺激。这种刺激被Smc3p与Scc2p界面的Eco1p乙酰化抑制。目前尚不清楚Scc2p如何刺激粘附素的ATPase活性，也不清楚乙酰化如何抑制Scc2p，因为乙酰化位点位于粘附素ATPase活性位点的远端。在这里，我们识别了萌芽酵母中的突变，这些突变抑制了由Smc3p乙酰模拟突变和乙酰缺陷突变引起的体内缺陷。我们提供了令人信服的证据，表明Scc2p对粘附素ATPase的激活依赖于Scc2p与粘附素Smc3p ATPase活性中心附近的Smc1p区域之间的界面。此外，这个界面上的替换增加或降低了ATPase的活性，以克服乙酰基模拟突变和乙酰零突变对ATPase的调节。利用这些观察结果和现有的低温EM结构，我们提出了一个调节粘附素ATPase活性的模型。我们认为，Scc2p与Smc1p结合导致相邻的Smc1p残基和ATP发生移位，刺激Smc3p的ATPase。这种刺激性转变通过Scc2p-Smc3p远端界面的乙酰化而被抑制。
In this study, Boardman et al. describe how interactions between auxiliary factor Scc2p and cohesin components Smc1p and Smc3p are crucial for the complex's ATPase activity. They propose a model in which Scc2p–Smc1p binding stimulates Smc3p's ATPase by shifting ATP into the active site, while Smc3p acetylation interferes with the Scc2p–Smc1p interface and inhibits ATPase activity. The evolutionarily conserved cohesin complex mediates sister chromatid cohesion and facilitates mitotic chromosome condensation, DNA repair, and transcription regulation. These biological functions require cohesin's two ATPases, formed by the Smc1p and Smc3p subunits. Cohesin's ATPase activity is stimulated by the Scc2p auxiliary factor. This stimulation is inhibited by Eco1p acetylation of Smc3p at an interface with Scc2p. It was unclear how cohesin's ATPase activity is stimulated by Scc2p or how acetylation inhibits Scc2p, given that the acetylation site is distal to cohesin's ATPase active sites. Here, we identify mutations in budding yeast that suppressed the in vivo defects caused by Smc3p acetyl-mimic and acetyl-defective mutations. We provide compelling evidence that Scc2p activation of cohesin ATPase depends on an interface between Scc2p and a region of Smc1p proximal to cohesin's Smc3p ATPase active site. Furthermore, substitutions at this interface increase or decrease ATPase activity to overcome ATPase modulation by acetyl-mimic and acetyl-null mutations. Using these observations and an existing cryo-EM structure, we propose a model for regulating cohesin ATPase activity. We suggest that Scc2p binding to Smc1p causes the adjacent Smc1p residues and ATP to shift, stimulating Smc3p's ATPase. This stimulatory shift is inhibited through acetylation of the distal Scc2p–Smc3p interface.
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