7myz
Structure of the full length 5-TM receptor CD47 bound to Fab B6H12
Structural highlights
FunctionC562_ECOLX Electron-transport protein of unknown function.CD47_HUMAN Has a role in both cell adhesion by acting as an adhesion receptor for THBS1 on platelets, and in the modulation of integrins. Plays an important role in memory formation and synaptic plasticity in the hippocampus (By similarity). Receptor for SIRPA, binding to which prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells. Interaction with SIRPG mediates cell-cell adhesion, enhances superantigen-dependent T-cell-mediated proliferation and costimulates T-cell activation. May play a role in membrane transport and/or integrin dependent signal transduction. May prevent premature elimination of red blood cells. May be involved in membrane permeability changes induced following virus infection.[1] [2] [3] Publication Abstract from PubMedCD47 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 SIRPalpha and inhibits macrophage phagocytosis, and cancer immuno-therapy approaches in clinical trials are focused on blocking CD47/SIRPalpha 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 ((114)RVVSWF(119)) 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. Structure of the human marker of self 5-transmembrane receptor CD47.,Fenalti G, Villanueva N, Griffith M, Pagarigan B, Lakkaraju SK, Huang RY, Ladygina N, Sharma A, Mikolon D, Abbasian M, Johnson J, Hadjivassiliou H, Zhu D, Chamberlain PP, Cho H, Hariharan K Nat Commun. 2021 Sep 1;12(1):5218. doi: 10.1038/s41467-021-25475-w. PMID:34471125[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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