GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase
GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase
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DOI：
10.1038/s41594-019-0249-3
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发表时间：
2019-07-01
影响因子：
16.8
通讯作者：
Pagano, Michele
中科院分区：
文献类型：
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作者：
Kuchay, Shafi;Wang, Hui;Pagano, Michele
蛋白质预烯基化被认为是由三种异二聚体酶催化的：FTase、GGTase1和GGTase2。在这里，我们报告了一个以前未知的人类戊烯基转移酶复合体的鉴定，该复合体由一个孤儿戊基转移酶α亚基PTAR1和GGTase2的催化β亚基RabGGTB组成。这种酶，我们将其命名为GGTase3，Geranylgeranylates Fbxl2，使其能够定位于细胞膜，其中这种泛素连接酶介导膜锚定蛋白的多泛素化。在细胞中，Fbxl2被GGTase3特异性识别，尽管有一个典型的羧基末端CAAX预烯化基序被GGTase1识别。我们对全长GGTase3-Fbxl2-Skp1复合体的晶体结构分析表明，在Fbxl2的富含亮氨酸的重复结构域和PTAR1之间形成了一个广泛的多价界面，揭示了底物-酶特异性的结构基础。通过发现一个缺失的戊烯基转移酶及其独特的底物识别模式，我们的发现呼吁对‘戊烯基化密码’进行修改。
Protein prenylation is believed to be catalyzed by three heterodimeric enzymes: FTase, GGTase1 and GGTase2. Here we report the identification of a previously unknown human prenyltransferase complex consisting of an orphan prenyltransferase alpha-subunit, PTAR1, and the catalytic beta-subunit of GGTase2, RabGGTB. This enzyme, which we named GGTase3, geranylgeranylates FBXL2 to allow its localization at cell membranes, where this ubiquitin ligase mediates the polyubiquitylation of membrane-anchored proteins. In cells, FBXL2 is specifically recognized by GGTase3 despite having a typical carboxy-terminal CaaX prenylation motif that is predicted to be recognized by GGTase1. Our crystal structure analysis of the full-length GGTase3-FBXL2-SKP1 complex reveals an extensive multivalent interface specifically formed between the leucine-rich repeat domain of FBXL2 and PTAR1, which unmasks the structural basis of the substrate-enzyme specificity. By uncovering a missing prenyltransferase and its unique mode of substrate recognition, our findings call for a revision of the 'prenylation code'.