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

Gustavo Fenalti (), Nicolas Villanueva, Mark Griffith, Barbra Pagarigan, Sirish Kaushik Lakkaraju, Richard Y.-C. Huang, Nadia Ladygina, Alok Sharma, David Mikolon, Mahan Abbasian, Jeffrey Johnson, Haralambos Hadjivassiliou, Dan Zhu, Philip P. Chamberlain, Ho Cho and Kandasamy Hariharan
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Gustavo Fenalti: Molecular Structure and Design, Bristol Myers Squibb
Nicolas Villanueva: Molecular Structure and Design, Bristol Myers Squibb
Mark Griffith: Protein Homeostasis, Bristol Myers Squibb
Barbra Pagarigan: Molecular Structure and Design, Bristol Myers Squibb
Sirish Kaushik Lakkaraju: Molecular Structure and Design, Bristol Myers Squibb
Richard Y.-C. Huang: Pharmaceutical Candidate Optimization, Nonclinical Research and Development, Bristol Myers Squibb
Nadia Ladygina: Pharmacology, Bristol Myers Squibb
Alok Sharma: Molecular Structure and Design, Bristol Myers Squibb
David Mikolon: Discovery Biotherapeutics, Bristol Myers Squibb
Mahan Abbasian: Discovery Biotherapeutics, Bristol Myers Squibb
Jeffrey Johnson: Discovery Biotherapeutics, Bristol Myers Squibb
Haralambos Hadjivassiliou: Discovery Biotherapeutics, Bristol Myers Squibb
Dan Zhu: Discovery Biotherapeutics, Bristol Myers Squibb
Philip P. Chamberlain: Protein Homeostasis, Bristol Myers Squibb
Ho Cho: Discovery Biotherapeutics, Bristol Myers Squibb
Kandasamy Hariharan: Discovery Biotherapeutics, Bristol Myers Squibb

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25475-w

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