COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes

COMMD1 is a member of a family of 10 copper metabolism MURR1 domain-containing proteins that have pleiotropic roles in copper metabolism, NF kappa beta-mediated transcription, the hypoxic response and electrolyte transport (Burstein et al, 2005; reviewed in Maine and Burstein, 2007). COMMD proteins have differential tissue and expression levels, but appear to have partially overlapping function and form homo- and heterodimers through the shared COMM domain (Burstein et al, 2005). COMMD1 and other family members interact with the cullin subunit of CRL E3 ubiquitin ligase complexes, as well as with CCDC22, a protein implicated in X-linked intellectual disability that may regulate COMMD localization. Together, COMMD proteins and CCDC22 activate the ubiquitin ligase activity of CRL complexes by displacing the CAND1 inhibitor (Burstein et al, 2005; Maine et al, 2007; Mao et al, 2011; Starokadomskyy et al, 2013;Phillips-Krawczak et al, 2015). The specificity of interaction between various COMMD and CUL family members may serve to fine tune the regulation of CRL activation, although these details remain to be determined.

COMMD1属铜代谢MURR1结构域蛋白家族成员之一，该家族包含10个成员，在铜代谢、NF-κB介导的转录、缺氧反应及电解质转运等生理过程中发挥多效性作用（Burstein等，2005；Maine和Burstein，2007综述）。COMMD蛋白在组织分布和表达水平上存在差异，但似乎在功能上部分重叠，并通过共同的COMM结构域形成同源和异源二聚体（Burstein等，2005）。COMMD1及其家族成员与CRL E3泛素连接酶复合物的cullin亚基以及与X连锁智力障碍相关的CCDC22蛋白相互作用，后者可能调节COMMD蛋白的定位。COMMD蛋白与CCDC22共同通过移除CAND1抑制剂激活CRL复合物的泛素连接酶活性（Burstein等，2005；Maine等，2007；Mao等，2011；Starokadomskyy等，2013；Phillips-Krawczak等，2015）。COMMD与CUL家族成员之间相互作用的特异性可能有助于精细调节CRL活化的调控，尽管这些细节尚待确定。