Functional Elements on SIRPα IgV Domain Mediate Cell Surface Binding to CD47

Yuan Liu, Qiao Tong, Yubin Zhou, Hsiau Wei Lee, Jenny J. Yang, Hans Jörg Bühring, Yi Tien Chen, Binh Ha, Celia X.J. Chen, Yang Yang, Ke Zen

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


SIRPα and SIRPβ1, the two major isoforms of the signal regulatory protein (SIRP) family, are co-expressed in human leukocytes but mediate distinct extracellular binding interactions and divergent cell signaling responses. Previous studies have demonstrated that binding of SIRPα with CD47, another important cell surface molecule, through the extracellular IgV domain regulates important leukocyte functions including macrophage recognition, leukocyte adhesion and transmigration. Although SIRPβ1 shares highly homologous extracellular IgV structure with SIRPα, it does not bind to CD47. Here, we defined key amino acid residues exclusively expressing in the IgV domain of SIRPα, but not SIRPβ1, which determine the extracellular binding interaction of SIRPα to CD47. These key residues include Gln67, a small hydrophobic amino acid (Ala or Val) at the 57th position and Met102. We found that Gln67 and Ala/Val57 are critical. Mutation of either of these residues abates SIRPα directly binding to CD47. Functional cell adhesion and leukocyte transmigration assays further demonstrated central roles of Gln67 and Ala/Val57 in SIRPα extracellular binding mediated cell interactions and cell migration. Another SIRPα-specific residue, Met102, appears to assist SIRPα IgV binding through Gln67 and Ala/Val57. An essential role of these amino acid residues in SIRPα binding to CD47 was further confirmed by introducing these residues into the SIRPβ1 IgV domain, which dramatically converts SIRPβ1 into a CD47-binding molecule. Our results thus revealed the molecular basis by which SIRPα binds to CD47 and shed new light into the structural mechanisms of SIRP isoform mediated distinctive extracellular interactions and cellular responses.

Original languageEnglish
Pages (from-to)680-693
Number of pages14
JournalJournal of Molecular Biology
Issue number3
Publication statusPublished - Jan 19 2007
Externally publishedYes


  • extracellular binding interaction
  • Ig superfamily protein
  • IgV domain
  • signal regulatory proteins

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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