Structure of the human marker of self 5-transmembrane receptor CD47

CD47 is the only 5-transmembrane (5-TM) spanning receptor of the immune system. Its extracellular domain (ECD) is a cell surface marker of self that binds SIRP alpha and inhibits macrophage phagocytosis, and cancer immuno-therapy approaches in clinical trials are focused on blocking CD47/SIRP alpha interaction. We present the crystal structure of full length CD47 bound to the function-blocking antibody B6H12. CD47 ECD is tethered to the TM domain via a six-residue peptide linker ((RVVSWF119)-R-114) that forms an extended loop (SWF loop), with the fundamental role of inserting the side chains of W118 and F119 into the core of CD47 extracellular loop region (ECLR). Using hydrogen-deuterium exchange and molecular dynamics simulations we show that CD47's ECLR architecture, comprised of two extracellular loops and the SWF loop, creates a molecular environment stabilizing the ECD for presentation on the cell surface. These findings provide insights into CD47 immune recognition, signaling and therapeutic intervention. CD47 is a transmembrane receptor involved in the regulation of various signalling pathways and a promising target for immuno-oncology therapeutics. Here, the authors present the crystal structure of full-length human CD47 and provide insights into the molecular mechanism of CD47-mediated signalling.

Automated summary

CD47 is the only 5-TM spanning receptor of the immune system, with its ECD serving as a cell surface marker of self that binds SIRP alpha and inhibits macrophage phagocytosis. The crystal structure of CD47 bound to the function-blocking antibody B6H12 provides insights into its molecular mechanism.