Novel Structural Determinants on SIRPα that Mediate Binding to CD47

Journal of Immunology - Tập 179 Số 11 - Trang 7741-7750 - 2007
Winston Y. Lee1, Dominique A. Weber1, Oskar Laur2, Eric A. Severson1, Ingrid C. McCall1, Rita Jen1, Alex C. Chin1, Tao Wu1, Kim M. Gernet3, Charles A. Parkos1
1Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322
2*Emory Vaccine Center, Department of Microbiology and Immunology, Emory University, Atlanta, GA 30329; and
3‡BioMolecular Computing Resource, Emory University, Atlanta, GA 30322

Tóm tắt

Abstract Signal regulatory proteins (SIRP-α, -β, and -γ) are important regulators of several innate immune functions that include leukocyte migration. Membrane distal (D1) domains of SIRPα and SIRPγ, but not SIRPβ, mediate binding to a cellular ligand termed CD47. Because the extracellular domains of all SIRPs are highly homologous, we hypothesized that some of the 16 residues unique to SIRPα.D1 mediate binding to CD47. By site-directed mutagenesis, we determined that SIRPα binding to CD47 is independent of N-glycosylation. We also identified three residues critical for CD47 binding by exchanging residues on SIRPα with corresponding residues from SIRPβ. Cumulative substitutions of the critical residues into SIRPβ resulted in de novo binding of the mutant protein to CD47. Homology modeling of SIRPα.D1 revealed topological relationships among critical residues and allowed the identification of critical residues common to SIRPα and SIRPβ. Mapping these critical residues onto the recently reported crystal structure of SIRPα.D1 revealed a novel region that is required for CD47 binding and is distinct and lateral to another putative CD47 binding site described on that crystal structure. The importance of this lateral region in mediating SIRPα.D1 binding to CD47 was confirmed by epitope mapping analyses of anti-SIRP Abs. These observations highlight a complex nature of the ligand binding requirements for SIRPα that appear to be dependent on two distinct but adjacent regions on the membrane distal Ig loop. A better understanding of the structural basis of SIRPα/CD47 interactions may provide insights into therapeutics targeting pathologic inflammation.

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Journal of Immunology

Tập 179 Số 11

7741-7750

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