Structure of signal-regulatory protein alpha: a link to antigen receptor evolution.

Journal article

Signal-regulatory protein alpha (SIRPalpha) is a myeloid membrane receptor that interacts with the membrane protein CD47, a marker of self. We have solved the structure of the complete extracellular portion of SIRPalpha, comprising three immunoglobulin superfamily domains, by x-ray crystallography to 2.5 A resolution. These data, together with previous data on the N-terminal domain and its ligand CD47 (possessing a single immunoglobulin superfamily domain), show that the CD47-SIRPalpha interaction will span a distance of around 14 nm between interacting cells, comparable with that of an immunological synapse. The N-terminal (V-set) domain mediates binding to CD47, and the two others are found to be constant (C1-set) domains. C1-set domains are restricted to proteins involved in vertebrate antigen recognition: T cell antigen receptors, immunoglobulins, major histocompatibility complex antigens, tapasin, and beta2-microglobulin. The domains of SIRPalpha (domains 2 and 3) are structurally more similar to C1-set domains than any cell surface protein not involved in antigen recognition. This strengthens the suggestion from sequence analysis that SIRP is evolutionarily closely related to antigen recognition proteins.

Authors: Hatherley, D; Graham, S; Harlos, K; Stuart, D; Barclay, N

• Publication status: Published
• Journal: Journal of biological chemistry
• Volume: 284
• Issue: 39
• Pages: 26613-26619
• Publication date: 2009-09-01
• DOI: 10.1074/jbc.m109.017566
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Sequence Homology, Amino Acid; Protein Conformation; Protein Structure, Tertiary; Receptors, Immunologic; Humans; Antigens, Differentiation; Amino Acid Sequence; Cricetinae; Models, Molecular; CHO Cells; Evolution, Molecular; Antigens, CD47; Cricetulus; Crystallography, X-Ray; Molecular Sequence Data; Protein Structure, Secondary; Animals; Protein Binding; Cluster Analysis; Binding Sites