Structure of a complex of CD47 and the paired receptor SIRPa reveals a mechanism for ligand discrimination

Authors: D. Hatherley (University of Oxford) , S. C. Graham (Wellcome Trust Centre for Human Genetics, University of Oxford) , J. Turner (University of Oxford) , K. Harlos (Wellcome Trust Centre for Human Genetics, University of Oxford) , A. N. Barclay (University of Oxford) , D. I. Stuart (Wellcome Trust Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Conference Paper
Conference: Annual Congress of the British Society for Immunology, 17-21 November, Glasgow, UK
Peer Reviewed: No

State: Published (Approved)
Published: November 2008

Abstract: Signal regulatory protein alpha (SIRPa gives inhibitory signals to myeloid cells upon engagement with the broadly distributed cell surface protein CD47. SIRP is a "paired receptor" having a closely related gene encoding a membrane protein (SIRP) that associates with the adapter protein DAP12 to give potential activating signals. However, SIRP( shows negligible binding to the SIRP( ligand CD47 despite up to 90% sequence identity in the ligand binding domains. A third closely related gene encodes SIRP( which can interact with CD47 but has no apparent signalling capability itself. To understand the structural basis for the SIRP paired receptor interactions high-resolution X-ray crystallographic structures of the following immunoglobulin superfamily domains were determined: (1) CD47 alone and in complex with the Nterminal ligand-binding domain of SIRPa and (2) the N-terminal domains of SIRPb, SIRPb(2) and SIRPc.These studies reveal how the loops at the end of the SIRPa domain interdigitate with the convoluted interacting face of CD47. This mode of binding is analogous to the complementarity determining loops of antigen receptors such as the T cell receptor interacting with MHC. The failure of the SIRPb proteins to bind is due to subtle differences in the loops.

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Added On: 13/05/2010 10:26

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