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Instruments / Technical Area	Publication Details	Published
I04-1-Macromolecular Crystallography (fixed wavelength)	Structures of CD6 and its ligand CD166 give insight into their interaction Paul Chappell , Lee i. Garner , Jun Yan , Clive Metcalfe , Deborah Hatherley , Steven Johnson , Carol v. Robinson , Susan Lea , Marion h. Brown Structure 23 (8), 1426 - 1436 DOI: 10.1016/j.str.2015.05.019 PMID: 26146185 Diamond Proposal Number(s): [9306] Open Access Show Abstract ▼ Abstract: CD6 is a transmembrane protein with an extracellular region containing three scavenger receptor cysteine rich (SRCR) domains. The membrane proximal domain of CD6 binds the N-terminal immunoglobulin superfamily (IgSF) domain of another cell surface receptor, CD166, which also engages in homophilic interactions. CD6 expression is mainly restricted to T cells, and the interaction between CD6 and CD166 regulates T-cell activation. We have solved the X-ray crystal structures of the three SRCR domains of CD6 and two N-terminal domains of CD166. This first structure of consecutive SRCR domains reveals a nonlinear organization. We characterized the binding sites on CD6 and CD166 and showed that a SNP in CD6 causes glycosylation that hinders the CD6/CD166 interaction. Native mass spectrometry analysis showed that there is competition between the heterophilic and homophilic interactions. These data give insight into how interactions of consecutive SRCR domains are perturbed by SNPs and potential therapeutic reagents.	Jul 2015
I03-Macromolecular Crystallography	Crystal structure of signal regulatory protein gamma (SIRPγ) in complex with an antibody Fab fragment Joanne E. Nettleship , Jingshan Ren , David J. Scott , Nahid Rahman , Debbie Hatherley , Yuguang Zhao , David I. Stuart , A. Neil Barclay , Raymond J. Owens Bmc Structural Biology 13 DOI: 10.1186/1472-6807-13-13 PMID: 23826770 Open Access Show Abstract ▼ 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 (K d = 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.	Jul 2013
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structures of CD200/CD200 receptor family and implications for topology, regulation, and evolution Debbie Hatherley , Susan Lea , Steven Johnson , A. neil Barclay Structure DOI: 10.1016/j.str.2013.03.008 PMID: 23602662 Open Access Show Abstract ▼ Abstract: CD200 is a widely distributed membrane glycoprotein that regulates myeloid cell activity through its interaction with an inhibitory receptor (CD200R). The interaction is of interest as a target for treating excessive inflammation and for treating leukemia. There are closely related proteins to CD200R that give activating signals making this a “paired receptor.” We report X-ray crystallography structures for the inhibitory CD200R, the activating receptor CD200RLa, and a complex between CD200R and CD200. Both CD200 and CD200R contain two Ig-like domains and interact through their NH2 terminal domains compatible with immunological synapse-like interactions occurring between myeloid cells and other CD200-expressing cells. The failure of the activating receptor to bind CD200 resides in subtle changes around the interface. CD200 has been acquired by herpes viruses to mimic the host interaction. CD200R has evolved rapidly presumably driven by pathogen pressure but it may also be important in homeostasis through interactions with commensal bacteria.	Apr 2013
	Paired receptor specificity explained by structures of signal regulatory proteins alone and complexed with CD47 Debbie Hatherley , Jessie Turner , A. Neil Barclay , David I. Stuart , Karl Harlos , Stephen C. Graham Molecular Cell 31 (2), 266-277 DOI: 10.1016/j.molcel.2008.05.026 Show Abstract ▼ Abstract: CD47 is a widely distributed cell-surface protein that acts a marker of self through interactions of myeloid and neural cells. We describe the high-resolution Xray crystallographic structures of the immunoglobulin superfamily domain of CD47 alone and in complex with the N-terminal ligand-binding domain of signal regulatory protein alpha (SIRP alpha). The unusual and convoluted interacting face of CD47, comprising the N terminus and loops at the end of the domain, intercalates with the corresponding regions in SIRP alpha. We have also determined structures of the N-terminal domains of SIRP beta, SIRP beta(2), and SIRP gamma; proteins that are closely related to SIR alpha but bind CD47 with negligible or reduced affinity. These results explain the specificity of CD47 for the SIRP family of paired receptors in atomic detail. Analysis of SIRP alpha polymorphisms suggests that these, as well as the activating SIRPs, may have evolved to counteract pathogen binding to the inhibitory SIRP alpha receptor.	Jul 2008

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