A basis for new approaches to the chemotherapy of AIDS: novel genes in HIV-1 potentially encode selenoproteins expressed by ribosomal frameshifting and termination suppression.
A basis for new approaches to the chemotherapy of AIDS: novel genes in HIV-1 potentially encode selenoproteins expressed by ribosomal frameshifting and termination suppression.
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DOI：
10.1021/jm00043a004
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发表时间：
1994-08
影响因子：
7.3
通讯作者：
E. Taylor;C. Ramanathan;R. Jalluri;R. Nadimpalli
中科院分区：
文献类型：
--
作者：
E. Taylor;C. Ramanathan;R. Jalluri;R. Nadimpalli
通过分析人类免疫缺陷病毒1型（HIV-1）的基因组RNA结构及其与新的开放阅读框架的关系，发现了几个以前未被注意的基因，可能编码硒蛋白。我们已经发现了一些新的潜在的RNA假结，包括一个在长末端重复，几个符合高度保守的酶活性位点序列的pol编码区，和一个在env编码区。这些假结可以潜在地指导含硒代半胱氨酸（SeC）的-1移码融合蛋白的合成。这是可能的，因为我们已经在HIV和其他逆转录病毒的RNA中发现了潜在的SeC插入序列（SECIS）;已知这种结构对于在真核mRNA中任何地方的UGA“终止”密码子处掺入SeC是必要的和足够的。在几个地方，UGA密码子在-1阅读框架是高度保守的广泛的灵长类免疫缺陷病毒。由于遗传密码的简并性，这种保守性不能单独用pol基因蛋白质序列的进化选择来解释。这样的观察，结合相关的阅读框架的保守性，强烈表明这些是真实的基因，因此假结也是真实的。蛋白酶假结定向-1移码融合蛋白含有高度保守的SeC密码子，并与许多DNA结合蛋白（包括乳头瘤病毒E2蛋白）具有显著的相似性，这表明当被蛋白酶从gag-pol基因产物的其余部分切割时，它可能是HIV转录的病毒编码阻遏物。逆转录酶（RT）移码融合蛋白用高度保守的含SeC的模块替换RT活性位点。整合酶移码融合蛋白包含N末端整合酶DNA结合结构域和潜在的ATP结合“GKS”基序;它与几种解旋酶具有显着相似性，但没有SeC密码子。来自env的潜在移码融合蛋白具有一个SeC密码子，但不在高度保守的位置。SeC掺入可以通过C-末端UGA密码子将nef基因产物延长33个残基而不发生移码，可能导致感染细胞中大量的SeC利用。（400字处截断摘要）
Several previously unnoticed genes in the human immunodeficiency virus type 1 (HIV-1), potentially encoding selenoproteins, have been discovered by analyzing the genomic RNA structure and its relation to novel open reading frames. We have found a number of new potential RNA pseudoknots, including one in the long terminal repeat, several that coincide with highly conserved enzyme active site sequences in the pol coding region, and one in the env coding region. These pseudoknots can potentially direct the synthesis of selenocysteine (SeC) containing--1 frameshift fusion proteins. This is possible because we have found potential SeC insertion sequences (SECIS) in the RNA of HIV and other retroviruses; such structures are known to be necessary and sufficient for the incorporation of SeC at UGA "stop" codons anywhere in a eukaryotic mRNA. In several locations, UGA codons in the -1 reading frame are highly conserved across a broad spectrum of primate immunodeficiency viruses. Due to the degeneracy of the genetic code, this conservation cannot be explained by evolutionary selection of the pol gene protein sequence alone. Such observations, combined with the conservation of the associated reading frames, strongly suggest that these are real genes, and thus that the pseudoknots are also real. A protease pseudoknot-directed -1 frameshift fusion protein contains a highly conserved SeC codon and has significant similarities to a number of DNA binding proteins, including papillomavirus E2 proteins, suggesting it may be a virally encoded repressor of HIV transcription when cleaved by protease from the rest of the gag-pol gene product. A reverse transcriptase (RT) frameshift fusion protein replaces the RT active site with a highly conserved SeC-containing module. An integrase frameshift fusion protein contains the N-terminal integrase DNA-binding domain and a potential ATP-binding "GKS" motif; it has significant similarities to several helicases, but no SeC codons. A potential frameshift fusion protein from env has one SeC codon, but not in a highly conserved position. SeC incorporation could extend the nef gene product by 33 residues through the C-terminal UGA codon without frameshifting, potentially leading to substantial SeC utilization in infected cells.(ABSTRACT TRUNCATED AT 400 WORDS)