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

DOI: 10.1038/s41467-021-25475-w DOI Help

Authors: Gustavo Fenalti (Bristol Myers Squibb) , Nicolas Villanueva (Bristol Myers Squibb) , Mark Griffith (Bristol Myers Squibb) , Barbra Pagarigan (Bristol Myers Squibb) , Sirish Kaushik Lakkaraju (Bristol Myers Squibb) , Richard Y.-C. Huang (Bristol Myers Squibb) , Nadia Ladygina (Bristol Myers Squibb) , Alok Sharma (Bristol Myers Squibb) , David Mikolon (Bristol Myers Squibb) , Mahan Abbasian (Bristol Myers Squibb) , Jeffrey Johnson (Bristol Myers Squibb) , Haralambos Hadjivassiliou (Bristol Myers Squibb) , Dan Zhu (Bristol Myers Squibb) , Philip P. Chamberlain (Bristol Myers Squibb) , Ho Cho (Bristol Myers Squibb) , Kandasamy Hariharan (Bristol Myers Squibb)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: September 2021

Open Access Open Access

Abstract: 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 SIRPα and inhibits macrophage phagocytosis, and cancer immuno-therapy approaches in clinical trials are focused on blocking CD47/SIRPα 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 (114RVVSWF119) 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.

Journal Keywords: Membrane proteins; Signal transduction

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 06/09/2021 10:07

Documents:
s41467-021-25475-w.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)