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Structures of CD200/CD200 receptor family and implications for topology, regulation, and evolution.

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.

SUBMITTER: Hatherley D

PROVIDER: S-EPMC3664923 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Structures of CD200/CD200 receptor family and implications for topology, regulation, and evolution.

Hatherley Deborah D Lea Susan M SM Johnson Steven S Barclay A Neil AN

Structure (London, England : 1993) 20130418 5

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 ...[more]

PMID: 23602662

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Project description:In conjunction with the endothelin (ET) type A (ETAR) and type B (ETBR) receptors, angiotensin (AT) type 1 (AT1R) and type 2 (AT2R) receptors, are peptide-binding class A G-protein-coupled receptors (GPCRs) acting in a physiologically overlapping context. Angiotensin receptors (ATRs) are involved in regulating cell proliferation, as well as cardiovascular, renal, neurological, and endothelial functions. They are important therapeutic targets for several diseases or pathological conditions, such as hypertrophy, vascular inflammation, atherosclerosis, angiogenesis, and cancer. Endothelin receptors (ETRs) are expressed primarily in blood vessels, but also in the central nervous system or epithelial cells. They regulate blood pressure and cardiovascular homeostasis. Pathogenic conditions associated with ETR dysfunctions include cancer and pulmonary hypertension. While both receptor groups are activated by their respective peptide agonists, pathogenic autoantibodies (auto-Abs) can also activate the AT1R and ETAR accompanied by respective clinical conditions. To date, the exact mechanisms and differences in binding and receptor-activation mediated by auto-Abs as opposed to endogenous ligands are not well understood. Further, several questions regarding signaling regulation in these receptors remain open. In the last decade, several receptor structures in the apo- and ligand-bound states were determined with protein X-ray crystallography using conventional synchrotrons or X-ray Free-Electron Lasers (XFEL). These inactive and active complexes provide detailed information on ligand binding, signal induction or inhibition, as well as signal transduction, which is fundamental for understanding properties of different activity states. They are also supportive in the development of pharmacological strategies against dysfunctions at the receptors or in the associated signaling axis. Here, we summarize current structural information for the AT1R, AT2R, and ETBR to provide an improved molecular understanding.

Project description:The CD200-CD200R pathway is involved in inhibition of immune responses, and the importance of this pathway to infectious disease is highlighted by the fact that viral CD200 (vCD200) molecules have been found to be encoded by several DNA viruses, including the human gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV), and the closely related rhesus macaque rhadinovirus (RRV). KSHV vCD200 is the most extensively studied vCD200 molecule, however, the only herpesvirus vCD200 molecule to be examined in vivo is that encoded by RRV. Our prior studies have demonstrated that RRV vCD200 is a functional CD200 homologue that is capable of affecting immune responses in vivo, and further, that RRV can express a secreted form of vCD200 (vCD200-Sec) during infection. Despite this information, RRV vCD200 has not been examined specifically for effects on RM CD200R signaling, and the functionality of vCD200-Sec has not been examined in any context. Thus, we developed an in vitro model system in which B cells expressing vCD200 were utilized to assess the effects of this molecule on the regulation of myeloid cells expressing RM CD200R, mimicking interactions that are predicted to occur in vivo Our findings suggest that RRV vCD200 can bind and induce functional signals through RM CD200R, while vCD200-Sec represents a non-functional protein incapable of affecting CD200R signaling. We also provide the first demonstration of the function of RM CD200, which appears to possess more robust signaling capabilities than RRV vCD200, and also show that KSHV vCD200 does not efficiently induce signaling via RM CD200R.IMPORTANCE Viral CD200 homologues are encoded by KSHV and the closely related RRV. Though RRV vCD200 has been examined, questions still exist in regard to the ability of this molecule to induce signaling via rhesus macaque CD200R, as well as the potential function of a secreted form of vCD200. Further, all previous in vitro studies of RRV vCD200 have utilized an Fc fusion protein to examine functionality, which does not replicate the structural properties of the membrane-associated form of vCD200 that is naturally produced during RRV infection. In this study, we demonstrate for the first time that membrane-expressed RRV vCD200 is capable of inducing signal transduction via RM CD200R, while the secreted form of vCD200 appears to be non-functional. Further, we also demonstrate that RM CD200 induces signaling via RM CD200R, and is more robust than RRV vCD200, while KSHV vCD200 does not appear to induce efficient signaling via RM CD200R.

Dataset Information

Structures of CD200/CD200 receptor family and implications for topology, regulation, and evolution.

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Structures of CD200/CD200 receptor family and implications for topology, regulation, and evolution.

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