Structural Insight into the Specific Interaction between Murine SHPS-1/SIRPα and Its Ligand CD47
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- 作者：Aki Nakaishi ; Mayumi Hirose ; Masato Yoshimura ; Chitose Oneyama ; Kazunobu Saito ; Nobuharu Kuki ; Makoto Matsuda ; Nakayuki Honma ; Hiroshi Ohnishi ; Takashi Matozaki ; Masato Okada ; Atsushi Nakagawa
- 关键词：SHPS-1 ; SIRP family ; immunogloblin superfamily ; CD47 ; complementarity-determining regions
- 刊名：Journal of Molecular Biology
- 出版年：2008
- 出版时间：18 January 2008
- 年：2008
- 卷：375
- 期：3
- 页码：650-660
- 全文大小：1373 K
文摘
SRC homology 2 domain-containing protein tyrosine phosphatase substrate 1 (SHPS-1 or SIRPα/BIT) is an immunoglobulin (Ig) superfamily transmembrane receptor and a member of the signal regulatory protein (SIRP) family involved in cell–cell interaction. SHPS-1 binds to its ligand CD47 to relay an inhibitory signal for cellular responses, whereas SIRPβ, an activating member of the same family, does not bind to CD47 despite sharing a highly homologous ligand-binding domain with SHPS-1. To address the molecular basis for specific CD47 recognition by SHPS-1, we present the crystal structure of the ligand-binding domain of murine SHPS-1 (mSHPS-1). Folding topology revealed that mSHPS-1 adopts an I2-set Ig fold, but its overall structure resembles IgV domains of antigen receptors, although it has an extended loop structure (C′E loop), which forms a dimer interface in the crystal. Site-directed mutagenesis studies of mSHPS-1 identified critical residues for CD47 binding including sites in the C′E loop and regions corresponding to complementarity-determining regions of antigen receptors. The structural and functional features of mSHPS-1 are consistent with the human SHPS-1 structure except that human SHPS-1 has an additional β-strand D. These results suggest that the variable complementarity-determining region-like loop structures in the binding surface of SHPS-1 are generally required for ligand recognition in a manner similar to that of antigen receptors, which may explain the diverse ligand-binding specificities of SIRP family receptors.