MUTATIONAL ANALYSIS OF HIV-1 TAT MINIMAL DOMAIN PEPTIDES - IDENTIFICATION OF TRANS-DOMINANT MUTANTS THAT SUPPRESS HIV-LTR-DRIVEN GENE-EXPRESSION
MUTATIONAL ANALYSIS OF HIV-1 TAT MINIMAL DOMAIN PEPTIDES - IDENTIFICATION OF TRANS-DOMINANT MUTANTS THAT SUPPRESS HIV-LTR-DRIVEN GENE-EXPRESSION
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DOI：
10.1016/0092-8674(89)90417-0
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发表时间：
1989-07-14
期刊：
影响因子：
64.5
通讯作者：
LOEWENSTEIN, PM
中科院分区：
文献类型：
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作者：
GREEN, M;ISHINO, M;LOEWENSTEIN, PM
HIV-1Tat蛋白是一种有效的反式激活因子，对病毒复制至关重要。我们以前报道过，HIV-1Tat多肽含有37-48个残基(主要是II区)和49-57个残基(III区)，它们是一个可能的活化区，是一个核靶向和假定的核酸结合区，具有最小但明显的反式激活活性。残基58-72(区域IV)的存在极大地增强了反式激活。我们推测，Ta突变多肽具有非活性区域II和功能区域III，可以表现为显性负突变。我们合成了在不同HIV分离株之间保守的、含有II区氨基酸残基的单一氨基取代的最小结构域肽。我们确定了四个氨基酸残基，它们在Ta最小结构域肽中的替换导致反式激活缺陷。其中一些突变体在几个肽骨架上是反式显性的，因为它们强烈地抑制了野生型Tat蛋白加入细胞或从显微注射质粒中表达的反式激活。值得注意的是，整合的HIV-LTRCAT的反式激活被一些反式显性突变多肽阻断。这些结果为艾滋病治疗的发展提供了一种有吸引力的方法。
The HIV-1 Tat protein is a potent trans-activator esssential for virus replication. We reported previously that HIV-1 Tat peptides containing residues 37-48 (mainly region II), a possible activating region, and residues 49-57 (region III), a nuclear targeting and putative nucleic acid binding region, possess minimal but distinct trans-activator activity. The presence of residues 58-72 (region IV) greatly enhances trans-activation. We postulate that Ta mutant peptides with an inactive region II and a functional region III can behave as dominant negative mutants. We synthesized minimal domain peptides containing single amino substitutions for amino acid residues within region II that are conserved among different HIV isolates. We identify four amino acid residues whose substitution within Ta minimal domain peptides leads to defects in trans-activation. Some of these mutants are trans-dominant in several peptide backbones, since they strongly inhibit trans-activation by wild-type Tat protein added to cells or expressed from microinjected plasmid. Significantly, trans-activation of integrated HIV-LTRCAT Is blocked by some trans-dominant mutant peptides. These results suggest an attractive approach for the development of an AIDS therapy.