COMMD1 expression is controlled by critical residues that determine XIAP binding.
COMMD1 expression is controlled by critical residues that determine XIAP binding.
复制标题
DOI：
10.1042/bj20080854
复制
发表时间：
2009-01-15
影响因子：
4.1
通讯作者：
Burstein, Ezra
中科院分区：
文献类型：
--
作者：
Maine, Gabriel N.;Mao, Xicheng;Muller, Patricia A.;Komarck, Christine M.;Klomp, Leo W. J.;Burstein, Ezra
关键词：
含有COMM结构域的蛋白参与多种细胞过程，包括NF-κB调节、铜稳态、钠转运和对缺氧的适应。该家族中研究最多的成员是COMMD1，但对其调控知之甚少，只知道XIAP是其泛素连接酶。在这项研究中，我们发现COMMD1的COMM结构域是其与XIAP相互作用所必需的，其他含有COMM结构域的蛋白质也可以类似地与iap相互作用。在COMM结构域中发现两个保守的亮氨酸重复序列是XIAP结合所必需的。无法与XIAP结合的COMMD1突变体表现出基础泛素化的完全丧失和蛋白质的高度稳定性。为了强调iap介导的泛素化的重要性，我们发现野生型COMMD1的长期表达由于泛素化的增加而导致接近生理的蛋白水平，但是当表达不能结合XIAP的突变形式时，这种调节事件被规避。总之，我们的研究结果表明COMMD1的表达主要受蛋白泛素化控制，其与IAP蛋白的相互作用起着至关重要的作用。
COMM domain-containing (or COMMD) proteins participate in several cellular processes, ranging from NF-κB regulation, copper homeostasis, sodium transport and adaptation to hypoxia. The best studied member of this family is COMMD1, but relatively little is known about its regulation, except that XIAP functions as its ubiquitin ligase. In this study, we identified that the COMM domain of COMMD1 is required for its interaction with XIAP, and other COMM domain containing proteins can similarly interact with IAPs. Two conserved leucine repeats within the COMM domain were found to be critically required for XIAP binding. A COMMD1 mutant unable to bind to XIAP demonstrated complete loss of basal ubiquitination and great stabilization of the protein. Underscoring the importance of IAP-mediated ubiquitination, we found that long-term expression of wild-type COMMD1 results in nearly physiologic protein levels due to increased ubiquitination, but this regulatory event is circumvented when expressing a mutant form that cannot bind XIAP. Altogether, our findings indicate that COMMD1 expression is primarily controlled by protein ubiquitination and its interaction with IAP proteins plays an essential role.