The CCC complex and intracellular endosomal trafficking

M Healy, R Hall, R Ghai and B Collins

Institute of Molecular Biosciences

Copper metabolism MURR1 domain containing gene 1 (COMMD1) is the founding member of the COMMD protein family. This family consists of 10 proteins that are highly conserved and are found in all metazoan organisms. Each COMMD protein contains a C-terminal COMM domain, which facilitates protein-protein interactions, and an N-terminal domain which is thought to ascribe unique functions to each of the family members. COMMD1 is the most extensively investigated member of this family and has been shown to have roles in regulating NF-κB signalling and hypoxia adaptation. More recently, each of the COMMD proteins has been shown to interact with the coiled-coil domain containing proteins (CCDC) 22 and 93 to form the CCC-complex. This complex acts with other multisubunit protein complexes such as retromer and WASH to facilitate the recovery and recycling of transmembrane receptors from endosomal compartments to the plasma membrane. Given that each of the COMMD family members are able to interact with CCDC22 it is predicted that the CCC complex will have pleiotropic roles within the cell and its function will be required to maintain cellular homeostasis. To date this complex has been found to transport and interact with receptors critical to cellular development (NOTCH2), copper homeostasis (ATP7A) and cholesterol homeostasis (LDLR). In the current project we aim to characterise the interactions between members of the COMMD family, other CCC complex subunits and membrane lipids in order to further elucidate their role in membrane trafficking. Here we demonstrate that COMMD1 is able to interact directly with each of the COMMD proteins and also show that some COMMD proteins are able to interact with specific membrane phospholipids that likely control their intracellular localisation.