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

Healy M1, Hospenthal M2, Hall R1, Chilton M3, Chandra M1, Chen K1, Cullen P3, Lott S2, Collins B1 and Ghai R1

  1. Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, 4072, Australia.
  2. School of Biological Sciences, The University of Auckland, Auckland 1142, New Zealand.
  3. School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.

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 several human COMMD proteins, and determined structures of COMMD proteins using X-ray crystallography and X-ray scattering to define the core principles of their 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.