Structural insights into the architecture and membrane interactions of the conserved COMMD proteins

Abstract

The COMMD proteins are a conserved family of proteins with central roles in intracellular membrane trafficking and transcription. They form oligomeric complexes with each other and act as components of a larger assembly called the CCC complex, which is localized to endosomal compartments and mediates the transport of several transmembrane cargos. How these complexes are formed however is completely unknown. Here, we have systematically characterised the interactions between human COMMD proteins, and determined structures of COMMD proteins using X-ray crystallography and X-ray scattering to provide insights into the underlying mechanisms of homo- and heteromeric assembly. All COMMD proteins possess an α-helical N-terminal domain, and a highly conserved C-terminal domain that forms a tightly interlocked dimeric structure responsible for COMMD-COMMD interactions. The COMM domains also bind directly to components of CCC and mediate non-specific membrane association. Overall these studies show that COMMD proteins function as obligatory dimers with conserved domain architectures.

Towards a molecular understanding of endosomal trafficking by Retromer and Retriever

“…This FAM21 domain also binds to Retromer. (C) Structure of Commd9 based on crystal structures of the N‐terminal HN domain and dimeric C‐terminal COMM domain, and SAXS‐based low resolution modelling of the full‐length protein . The two subunits of the homodimer are coloured grey and pale blue.…”

“…The other components of the CCC complex are the 10 members of the Copper Metabolism MURR1 (Mouse U2af1‐rs1 region 1) (COMM) domain (COMMD) family. Each of these proteins possesses a highly conserved C‐terminal COMM domain, with an α‐helical N‐terminal (HN) domain that is more variable in sequence . The one exception is Commd6, which in humans appears to lack the HN domain, although it is present in Commd6 from other species.…”

“…The founding member of the family, Commd1, was originally identified as the causative gene in terrier dogs with copper toxicosis, and interacts with and traffics the Wilson Disease copper transport protein ATP7B and its homologue ATP7A . The assembly of the CCC sub‐complex is facilitated by the binding of the COMM domains of the COMMD proteins to the N‐terminal NN‐CH domains of CCDC22 and CCDC93 . The CCDC22‐CCDC93 complex also interacts with Retriever, as well as the WASH complex subunit FAM21 which is required for recruitment of the Commander complex to endosomes .…”

“…While much about the structure and function of the Commander complex remains unknown, recent work has begun to provide insights into the biochemical and structural characteristics of the COMMD subunits (Figure C) . Using co‐expression to reconstitute binary complexes it was found that virtually all COMMD family members can form both homo and heterodimers via their C‐terminal COMM domains.…”

“…The N‐terminal HN domain is attached to the dimeric COMM domain via a linker that is believed to allow for flexibility in the overall structures of the dimeric proteins (Figure C) . The HN domain is an all‐α‐helical globular structure, with no similarity to any other protein of known function.…”