The specificities of Kaposi's sarcoma-associated herpesvirus-encoded E3 ubiquitin ligases are determined by the positions of lysine or cysteine residues within the intracytoplasmic domains of their targets
The specificities of Kaposi's sarcoma-associated herpesvirus-encoded E3 ubiquitin ligases are determined by the positions of lysine or cysteine residues within the intracytoplasmic domains of their targets
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DOI：
10.1128/jvi.02264-07
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发表时间：
2008-04-01
影响因子：
5.4
通讯作者：
Coscoy, Laurent
中科院分区：
文献类型：
--
作者：
Cadwell, Ken;Coscoy, Laurent
卡波西肉瘤相关疱疹病毒编码两种同源E3连接酶，MIR 1和MIR 2，其介导几种细胞表面蛋白的泛素化和随后的下调，特别是主要组织相容性复合物I类（MHC-I）分子。我们以前已经表明，除了赖氨酸泛素化，MIR 1具有独特的能力，转移泛素。以半胱氨酸依赖性方式，将其转移到缺乏可用赖氨酸残基的MHC-I分子上。在这里，我们报告说，MIR 1活性是最大的赖氨酸或半胱氨酸残基被放置在约15个氨基酸远离跨膜结构域，而MIR 2优先目标残基，包括半胱氨酸，更接近跨膜结构域。因此，MIR 1和MIR 2可以根据赖氨酸或半胱氨酸残基的位置来区分它们的底物，这表明这些蛋白质已经进化到靶向不同的表面分子组。这些结果表明，底物内靶残基的位置是E3泛素连接酶特异性的重要决定因素。
Kaposi's sarcoma-associated herpesvirus encodes two homologous E3 ligases, MIR1 and MIR2, that mediate the ubiquitination and subsequent downregulation of several cell surface proteins, and in particular major histocompatibility complex class I (MHC-I) molecules. We have previously shown that, in addition to lysine ubiquitination, MIR1 has the unique ability of transferring ubiquitin. onto MHC-I molecules lacking available lysine residues, in a cysteine-dependent manner. Here we report that MIR1 activity is maximal when either a lysine or cysteine residue is placed approximately 15 amino acids away from the transmembrane domain, whereas MIR2 preferentially targets residues, including cysteines, that are closer to the transmembrane domain. Thus MIR1 and -2 can distinguish their substrates based on the position, of the lysine or cysteine residues, suggesting that these proteins have evolved to target different sets of surface molecules. These results indicate that the position of target residues within a substrate is an essential determinant of E3 ubiquitin ligase specificity.