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Crystal Structure of Signal Regulatory Protein Gamma in Complex with an Antibody Fab Fragment

Published: Tuesday, July 09, 2013
Last Updated: Tuesday, July 09, 2013
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This paper presents the X-ray crystal structure of the complete extracellular portion of SIRP? co-crystallized with the Fab fragment of the OX117 monoclonal antibody.

Abstract

Background
Signal Regulatory Protein γ (SIRPγ) is a member of a closely related family of three cell  surface receptors implicated in modulating immune/inflammatory responses. SIRPγ is  expressed on T lymphocytes where it appears to be involved in the integrin-independent  adhesion of lymphocytes to antigen-presenting cells. Here we describe the first full length  structure of the extracellular region of human SIRPγ.

Results
We obtained crystals of SIRPγ by making a complex of the protein with the Fab fragment of  the anti-SIRP antibody, OX117, which also binds to SIRPα and SIRPβ. We show that the  epitope for FabOX117 is formed at the interface of the first and second domains of SIRPγ and comprises residues which are conserved between all three SIRPs. The FabOX117  binding site is distinct from the region in domain 1 which interacts with CD47, the  physiological ligand for both SIRPγ and SIRPα but not SIRPβ. Comparison of the three  domain structures of SIRPγ and SIRPα showed that these receptors can adopt different  overall conformations due to the flexibility of the linker between the first two domains.  SIRPγ in complex with FabOX117 forms a dimer in the crystal. Binding to the Fab fixes the  position of domain 1 relative to domains 2/3 exposing a surface which favours formation of a  homotypic dimer. However, the interaction appears to be relatively weak since only  monomers of SIRPγ were observed in sedimentation velocity analytical ultracentrifugation of  the protein alone. Studies of complex formation by equilibrium ultracentrifugation showed  that only a 1:1 complex of SIRPγ: FabOX117 was formed with a dissociation constant in the  low micromolar range (Kd = 1.2 +/− 0.3 µM).

Conclusion
The three-domain extracellular regions of SIRPs are structurally conserved but show  conformational flexibility in the disposition of the amino terminal ligand-binding Ig domain  relative to the two membrane proximal Ig domains. Binding of a cross-reactive anti-SIRP Fab  fragment to SIRPγ stabilises a conformation that favours SIRP dimer formation in the crystal  structure, though this interaction does not appear sufficiently stable to be observed in  solution.

This article was published online in BMC Structural Biology and is free to access.


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