Structure of signal-regulatory protein alpha: a link to antigen receptor evolution.
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.
Hatherley
Deborah
D
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
Graham
Stephen C
SC
Harlos
Karl
K
Stuart
David I
DI
Barclay
A Neil
AN
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
D000943:Antigens, Differentiation; D051928:CD47 Antigen; C497894:CD47 protein, human; D011971:Receptors, Immunologic; C501920:SIRPA protein, human