Membrane trafficking through the endosomal network is a fundamental cellular process essential for maintaining cell function. During this process, proteins are either sorted to the lysosome for degradation or recycled from early endosomes to the plasma membrane or the trans-Golgi network. Dysregulation of membrane trafficking has been associated with various diseases, including neurodegenerative disorders, cancer, and infectious disease. The COMMD protein family (copper metabolism MURR1 domain (COMMD)) is highly conserved across eukaryotic multicellular organisms and plays important roles in endosomal sorting. Recent studies have shown that the ten eukaryotic COMMD family members (COMMD1-COMMD10) assemble into a single hetero-decameric ring embedded in a larger protein complex known as Commander, which is responsible for endosomal recycling of diverse transmembrane cargos. The conservation of a hetero-decameric ring is a rarity in biology (to the best of our knowledge the COMMD protein stand out as a singular example), we therefore wanted to investigate the evolutionary origins and diversification of the COMMD protein family.
Previous sequence-based searches have failed to identify any prokaryotic COMMD proteins or single eukaryotic precursor genes. In this study I have used structure-based methods including FoldSeek to identify ~500 COMMD-like proteins in archaea and bacteria. Using a combination of structural, biochemical and biophysical assays I was able to demonstrate that these COMMD-like proteins form beautiful homo-octa/decameric rings that are structurally like the complex found in metazoan species. Interestingly, further analysis of these COMMD-like proteins with phylogenetics (structural and sequence) suggest that the most likely origin of the COMMD protein family is from the bacterial clade Myxococcus. This novel discovery could be critical to offer new insights into the evolutionary history of eukaryotic membrane trafficking and the broader process of eukaryogenesis.