Molecular mechanism of distinct chemokine engagement and functional divergence of the human Duffy antigen receptor
A new study published in Cell by the group of Volodymyr Korkhov (IMBB, ETHZ & PSI) in collaboration with the group of Arun Shukla (IIT Kanpur) describes the structure of Duffy antigen receptor for chemokines, DARC.
DARC is a seven-transmembrane (7TM) protein expressed primarily at the surface of red blood cells. The protein is capable of promiscuous binding to multiple inflammatory and homeostatic chemokines. DARC serves as the basis of the Duffy blood group system in humans and acts as the primary attachment site for malarial parasite Plasmodium vivax and the pore-forming toxins secreted by Staphylococcus aureus.
The Korkhov group (Institute of Molecular Biology and Biophysics, ETH Zurich & Paul Scherrer Institute), in collaboration with the group of Arun Shukla (Indian Institute of Technology Kanpur) determined the cryo-electron microscopy (cryo-EM) structure of DARC bound to its chemokine ligand, CCL7. The study includes a comprehensive analysis of transducer coupling of DARC and uncovered potential links of DARC to noncanonical cellular signaling pathways. The structure of DARC revealed a unique cytokine binding mode, featuring relatively superficial binding and a partially formed orthosteric binding pocket of the receptor. The TM5 and TM6 of DARC are shortened on the intracellular side, precluding the formation of the docking site for canonical signal transducers. These findings provide a possible explanation for the distinct pharmacological and functional properties of DARC.
Link to the paper in external page "Cell".