Human polycomb 2 protein is a SUMO E3 ligase and alleviates substrate-induced inhibition of cystathionine beta-synthase sumoylation.
Human polycomb 2 protein is a SUMO E3 ligase and alleviates substrate-induced inhibition of cystathionine beta-synthase sumoylation.
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DOI：
10.1371/journal.pone.0004032
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Banerjee, Ruma
中科院分区：
文献类型：
--
作者：
Agrawal, Nitish;Banerjee, Ruma
人胱硫醚β-合酶（CBS）催化转硫途径中的第一个不可逆步骤，并将高半胱氨酸转化为半胱氨酸。CBS突变是严重遗传性高同型半胱氨酸血症的最常见原因。一种酵母双杂交方法筛选与CBS相互作用的蛋白质，以前已经确定了sumoylation途径的几个组成部分，并证明CBS是sumoylation的底物。在这项研究中，我们证明，在人类polycomb组蛋白2（hPc 2），在最初的酵母双杂交筛选中确定的相互作用的合作伙伴的存在下，CBS的sumoylation增强。当CBS的底物，用于产生胱硫醚的同型半胱氨酸和丝氨酸以及用于产生H2S的同型半胱氨酸和半胱氨酸加入到类小泛素化混合物中时，它们抑制类小泛素化反应，但仅在不存在hPc 2的情况下。类似地，CBS反应的产物胱硫醚在不存在hPc 2的情况下抑制类小泛素化。在不存在hPc 2的情况下，类小泛素化反过来使CBS活性降低28%，在其存在下降低70%。基于这些结果，我们得出结论，hPc 2作为一个SUMO E3连接酶的CBS，提高sumoylation的效率。我们还证明，在转硫途径中的第二种酶γ-胱硫醚酶是在体外条件下sumoylation的底物。我们推测，这种修饰的作用可能是在核谷胱甘肽需求高的条件下，半胱氨酸生成途径的核定位。
Human cystathionine β-synthase (CBS) catalyzes the first irreversible step in the transsulfuration pathway and commits homocysteine to the synthesis of cysteine. Mutations in CBS are the most common cause of severe hereditary hyperhomocysteinemia. A yeast two-hybrid approach to screen for proteins that interact with CBS had previously identified several components of the sumoylation pathway and resulted in the demonstration that CBS is a substrate for sumoylation. In this study, we demonstrate that sumoylation of CBS is enhanced in the presence of human polycomb group protein 2 (hPc2), an interacting partner that was identified in the initial yeast two-hybrid screen. When the substrates for CBS, homocysteine and serine for cystathionine generation and homocysteine and cysteine for H2S generation, are added to the sumoylation mixture, they inhibit the sumoylation reaction, but only in the absence of hPc2. Similarly, the product of the CBS reaction, cystathionine, inhibits sumoylation in the absence of hPc2. Sumoylation in turn decreases CBS activity by ∼28% in the absence of hPc2 and by 70% in its presence. Based on these results, we conclude that hPc2 serves as a SUMO E3 ligase for CBS, increasing the efficiency of sumoylation. We also demonstrate that γ-cystathionase, the second enzyme in the transsulfuration pathway is a substrate for sumoylation under in vitro conditions. We speculate that the role of this modification may be for nuclear localization of the cysteine-generating pathway under conditions where nuclear glutathione demand is high.
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