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Protein Farnesyltransferase Catalyzes Unanticipated Farnesylation and Geranylgeranylation of Shortened Target Sequences.
Biochemistry ( IF 2.9 ) Pub Date : 2020-03-10 , DOI: 10.1021/acs.biochem.0c00081 Sudhat Ashok 1 , Emily R Hildebrandt 2 , Colby S Ruiz 2 , Daniel S Hardgrove 2 , David W Coreno 1 , Walter K Schmidt 2 , James L Hougland 1, 3
Biochemistry ( IF 2.9 ) Pub Date : 2020-03-10 , DOI: 10.1021/acs.biochem.0c00081 Sudhat Ashok 1 , Emily R Hildebrandt 2 , Colby S Ruiz 2 , Daniel S Hardgrove 2 , David W Coreno 1 , Walter K Schmidt 2 , James L Hougland 1, 3
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Protein prenylation is a posttranslational modification involving the attachment of a C15 or C20 isoprenoid group to a cysteine residue near the C-terminus of the target substrate by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type I (GGTase-I), respectively. Both of these protein prenyltransferases recognize a C-terminal "CaaX" sequence in their protein substrates, but recent studies in yeast- and mammalian-based systems have demonstrated FTase can also accept sequences that diverge in length from the canonical four-amino acid motif, such as the recently reported five-amino acid C(x)3X motif. In this work, we further expand the substrate scope of FTase by demonstrating sequence-dependent farnesylation of shorter three-amino acid "Cxx" C-terminal sequences using both genetic and biochemical assays. Strikingly, biochemical assays utilizing purified mammalian FTase and Cxx substrates reveal prenyl donor promiscuity leading to both farnesylation and geranylgeranylation of these sequences. These findings expand the substrate pool of sequences that can be potentially prenylated, further refine our understanding of substrate recognition by FTase and GGTase-I, and suggest the possibility of a new class of prenylated proteins within proteomes.
中文翻译：
蛋白法呢基转移酶催化未预期的法呢基化和短的靶序列的香叶基香叶基化。
蛋白质异戊二烯化是翻译后修饰，其涉及分别通过I类法呢基转移酶（FTase）或I类geranylgeranyltransferase I（GGTase-I）蛋白质将C15或C20类异戊二烯基团附着到目标底物C末端附近的半胱氨酸残基。这两种蛋白质异戊二烯基转移酶均识别其蛋白质底物中的C端“ CaaX”序列，但最近在基于酵母和哺乳动物的系统中的研究表明FTase也可以接受长度不同于标准四氨基酸基序的序列，例如最近报道的五氨基酸C（x）3X基序。在这项工作中，我们通过使用遗传和生物化学分析方法证明较短的三氨基酸“ Cxx” C端序列的序列依赖性法尼基化，进一步扩大了FTase的底物范围。令人惊讶的是，利用纯化的哺乳动物FTase和Cxx底物进行的生化分析显示，异戊二烯供体的混杂导致了这些序列的法呢基化和香叶基香叶基化。这些发现扩大了可能被烯丙基化的序列的底物库，进一步完善了我们对FTase和GGTase-I对底物识别的理解，并暗示了蛋白质组中一类新型的烯丙基化蛋白的可能性。
更新日期：2020-03-10
中文翻译：
蛋白法呢基转移酶催化未预期的法呢基化和短的靶序列的香叶基香叶基化。
蛋白质异戊二烯化是翻译后修饰，其涉及分别通过I类法呢基转移酶（FTase）或I类geranylgeranyltransferase I（GGTase-I）蛋白质将C15或C20类异戊二烯基团附着到目标底物C末端附近的半胱氨酸残基。这两种蛋白质异戊二烯基转移酶均识别其蛋白质底物中的C端“ CaaX”序列，但最近在基于酵母和哺乳动物的系统中的研究表明FTase也可以接受长度不同于标准四氨基酸基序的序列，例如最近报道的五氨基酸C（x）3X基序。在这项工作中，我们通过使用遗传和生物化学分析方法证明较短的三氨基酸“ Cxx” C端序列的序列依赖性法尼基化，进一步扩大了FTase的底物范围。令人惊讶的是，利用纯化的哺乳动物FTase和Cxx底物进行的生化分析显示，异戊二烯供体的混杂导致了这些序列的法呢基化和香叶基香叶基化。这些发现扩大了可能被烯丙基化的序列的底物库，进一步完善了我们对FTase和GGTase-I对底物识别的理解，并暗示了蛋白质组中一类新型的烯丙基化蛋白的可能性。
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