title: Structure of signal-regulatory protein alpha: a link to antigen receptor evolution.
abstract: 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.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hatherley
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Graham
authors.forename: Karl
authors.initials: K
authors.lastname: Harlos
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.forename: A Neil
authors.initials: AN
authors.lastname: Barclay
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D051928:CD47 Antigen / Q000737:chemistry / Q000378:metabolism*; D016466:CHO Cells; D016000:Cluster Analysis; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D000943:Antigens, Differentiation; D051928:CD47 Antigen; C497894:CD47 protein, human; D011971:Receptors, Immunologic; C501920:SIRPA protein, human