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J. Biol. Chem., Vol. 282, Issue 19, 14567-14575, May 11, 2007

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The Structure of the Macrophage Signal Regulatory Protein (SIRP) Inhibitory Receptor Reveals a Binding Face Reminiscent of That Used by T Cell Receptors^*

Deborah Hatherley¹, Karl Harlos¹, D. Cameron Dunlop², David I. Stuart¹, and A. Neil Barclay¹³

From the Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE and Division of Structural Biology and the Oxford Protein Production Facility, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom

Signal regulatory protein (SIRP) is a membrane receptor that sends inhibitory signals to myeloid cells by engagement of CD47. The high resolution x-ray structure of the N-terminal ligand binding domain shows it to have a distinctive immunoglobulin superfamily V-like fold. Site-directed mutagenesis suggests that CD47 is bound at a surface involving the BC, FG, and DE loops, which distinguishes it from other immunoglobulin superfamily surface proteins that use the faces of the fold, but resembles antigen receptors. The SIRP interaction is confined to a single domain, and its use of an extended DE loop strengthens the similarity with T cell receptor binding and the suggestion that they are closely related in evolution. The employment of loops to form the CD47-binding surface provides a mechanism for small sequence changes to modulate binding specificity, explaining the different binding properties of SIRP family members.

Received for publication, December 15, 2006 , and in revised form, March 13, 2007.

The atomic coordinates and structure factors (code 2uv3) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Medical Research Council.

² Supported by a Wellcome Trust studentship.

³ To whom correspondence should be addressed. Tel.: 441865275598; Fax: 441865275591; E-mail: neil.barclay{at}path.ox.ac.uk.

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