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

Hatherley, Deborah; Harlos, K.; Dunlop, D. Cameron; Stuart, David I.; Barclay, A. Neil

doi:10.1074/jbc.m611511200

Cited by 71 publications

(114 citation statements)

References 64 publications

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“…As expected from the sequence similarity of the SIRPα and SIRPβ there is little difference in the overall structures of the domains but subtle differences in the loops were found with evidence for considerable mobility in these [17]. Sequence analysis and mutagenesis have failed to provide a simple explanation for the failure of SIRPβ to bind to CD47 [14,15,[17][18][19] but the structures suggest that this failure is due to subtle differences in the loops and involving indirect changes and not solely contact residues [17].…”

Section: The Structure Of Sirpα and Its Ligand Cd47mentioning

confidence: 88%

“…X-ray crystallography structures have been determined for the ligand binding domain of mouse, rat and human SIRPα [14][15][16], the single IgSF domain of CD47, a complex of SIRPα domain 1 and CD47, the N terminal domains of two alleles of SIRPβ (the activating receptor) and SIRPγ [16] and a NMR structure for SIRPβ (Protein Data Bank Code; 2D9C). The interacting domains are typical IgSF V-set domains but the binding site of SIRPα is highly convoluted and made up from loops at the end of the domain in a manner analogous to binding of antigens by immunoglobulins and the T cell receptor rather than involving the faces of the domain as in most cell cell interaction proteins (see [17]).…”

Section: The Structure Of Sirpα and Its Ligand Cd47mentioning

confidence: 99%

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Signal regulatory protein alpha (SIRPα)/CD47 interaction and function

Barclay

2009

Current Opinion in Immunology

103

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SummarySIRPα is an inhibitory receptor present on myeloid cells that interacts with a widely distributed membrane protein CD47. The activating member SIRPβ, despite extensive sequence similarity to SIRPα in the extracellular region, shows negligible binding to CD47. The SIRPα / CD47 interaction is unusual in that it can lead to bidirectional signalling through both SIRPα and CD47. This review concentrates on the interactions of SIRPα with CD47 where recent data have shed light on the structure of the proteins including determining why the activating SIRPβ does not bind CD47, evidence of extensive polymorphisms and implication for the evolution and function of this protein and paired receptors in general. The interaction may be modified by endocytosis of the receptors, cleavage by proteolysis and through interactions of surfactant proteins.

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Section: The Structure Of Sirpα and Its Ligand Cd47mentioning

confidence: 88%

Section: The Structure Of Sirpα and Its Ligand Cd47mentioning

confidence: 99%

Signal regulatory protein alpha (SIRPα)/CD47 interaction and function

Barclay

2009

Current Opinion in Immunology

103

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“…A previous study reported that soluble SIRP␥ binds to CD47 with a lower affinity compared with SIRP␣ using BIAcore analysis. 15,16,29 However, it has not been established what role SIRP␥ plays in T-cell recruitment. Here, we show that the recombinant CD47-AP fusion protein supports robust CD3 ϩ T-cell adhesion despite the low binding affinity reported.…”

mentioning

confidence: 99%

Endothelial CD47 interaction with SIRPγ is required for human T-cell transendothelial migration under shear flow conditions in vitro

Stefanidakis

Newton

Lee

et al. 2008

Blood

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Leukocyte transendothelial migration (TEM) is a critical event during inflammation. CD47 has been implicated in myeloid cell migration across endothelium and epithelium. CD47 binds to signal regulatory protein (SIRP), SIRP␣ and SIRP␥. So far, little is known about the role of endothelial CD47 in T-cell TEM in vivo or under flow conditions in vitro. Fluorescence-activated cell sorting and biochemical analysis show that CD3 ؉ T cells express SIRP␥ but not SIRP␣, and fluorescence microscopy showed that CD47 was enriched at endothelial junctions. These expression patterns suggested that CD47 plays a role in T-cell TEM through binding interactions with SIRP␥. We tested, therefore, whether CD47-SIRP␥ interactions affect T-cell transmigration using blocking mAb against CD47 or SIRP␥ in an in vitro flow model. These antibodies inhibited T-cell TEM by 70% plus or minus 6% and 82% plus or minus 1%, respectively, but had no effect on adhesion. In agreement with human mAb studies, transmigration of murine wild-type T helper type 1 cells across TNF-␣-activated murine CD47 ؊/؊ endothelium was reduced by 75% plus or minus 2% even though murine T cells appear to lack SIRP␥. Nonetheless, these findings suggest endothelial cell CD47 interacting with T-cell ligands, such as SIRP␥, play an important role in T-cell transendothelial migration. (Blood. 2008; 112:1280-1289) IntroductionRecruitment of leukocytes from the bloodstream into tissues during an inflammatory response involves a multistep adhesive and signaling cascade composed of selectin-mediated rolling and initial attachment, subsequent integrin-mediated arrest and migration on the apical surface, followed by transendothelial migration (TEM; diapedesis). 1 TEM involves multiple adhesion molecule pathways such as intracellular adhesion molecule (ICAM)-1-CD18, vascular cell adhesion molecule (VCAM)-1-VLA-4, CD47, platelet endothelial cell adhesion molecule (PECAM)-1, CD99, endothelial cell adhesion molecule (ESAM), junctional adhesion molecules (JAMs), and DNAX accessory molecule 1 [CD226]-polio virus receptor [CD155] (DNAM-1-PVR), although the cellular mechanisms controlling TEM are incompletely understood. 2 CD47 or integrin-associated protein (IAP) belongs to the immunoglobulin superfamily (IgSF) and is highly expressed in most cell types. It is a 50-kDa transmembrane protein that consists of an extracellular amino-terminal Ig domain, 5 highly hydrophobic putative membrane-spanning segments, and a short cytoplasmic tail. 3 CD47 has been shown to associate with integrins at the cell surface and signal through G-coupled proteins. 4 Important cellular ligands for CD47 are the signal regulatory proteins (SIRPs) SIRP␣ and SIRP␥. The SIRPs comprise a family of several transmembrane glycoproteins that belong to the IgSF and are present in the immune and central nervous system. 5 Each molecule contains 3 homologous extracellular Ig-like domains with distinct transmembrane and cytoplasmic domains. SIRP␣ was the first member to be identified and was detected on hematopoietic progeni...

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“…These are typified in the CD2:CD58 pair 26 where some 1200 Å 2 of surface area are buried in a relatively flat interface within the complex. A recent exception is the SIRPα receptor which instead uses the complementarity-determining loop regions as the adhesion site, although these are at the amino terminal end of the receptor and assumed to be furthermost from the cell membrane 52 . Nonetheless, these and similar electrostatic interactions frequently generate only low-affinity binding.…”

Section: Discussionmentioning

confidence: 99%

“…A common feature of cell-cell adhesion pairs for which structures are available is the exploitation of the broad faces presented by amino-terminal IgSF domains (usually formed by the C"C'CFG sheet) to generate extensive contact surfaces 52 . These are typified in the CD2:CD58 pair 26 where some 1200 Å 2 of surface area are buried in a relatively flat interface within the complex.…”

Section: Discussionmentioning

confidence: 99%

The Laminin 511/521 Binding Site on the Lutheran Blood Group Glycoprotein is Located at theFlexible Junction of Ig Domains 2 and 3

Mankelow¹

2007

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Word Count 185 Total Word Count:4960 2 AbstractThe Lutheran blood group glycoprotein, first discovered on erythrocytes, is widely expressed in human tissues. It is a ligand for the α α α α5 subunit of Laminin 511/521, an extracellular matrix protein. This interaction may contribute to vasocclusive events that are an important cause of morbidity in sickle cell disease. Using X-ray crystallography, small angle X-ray scattering and site directed mutagenesis we show that the extracellular region of Lutheran forms an extended structure with a distinctive bend between the second and third immunoglobulin-like domains. The linker between domains 2 and 3 appears to be flexible and is a critical determinant in maintaining an overall conformation for Lutheran that is capable of binding to Laminin. Mutagenesis studies indicate that Asp312 of Lutheran and the surrounding cluster of negatively charged residues in this linker region form the Laminin binding site. Unusually, receptor binding is therefore not a function of the domains expected to be furthermost from the plasma membrane. These studies imply that structural flexibility of Lutheran may be essential for its interaction with Laminin and present a novel opportunity for the development of therapeutics for sickle cell disease.

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

Cited by 71 publications

References 64 publications

Signal regulatory protein alpha (SIRPα)/CD47 interaction and function

Signal regulatory protein alpha (SIRPα)/CD47 interaction and function

Endothelial CD47 interaction with SIRPγ is required for human T-cell transendothelial migration under shear flow conditions in vitro

The Laminin 511/521 Binding Site on the Lutheran Blood Group Glycoprotein is Located at theFlexible Junction of Ig Domains 2 and 3

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