SurveyThe Class II cytokine receptor (CRF2) family: overview and patterns of receptor–ligand interactions
Introduction
The cytokine receptors form a structural family that can be divided into two classes based on conserved features in the extracellular domains (ECDs), particularly the number and spacing of cysteine and proline residues [1], [2]. This classification promoted investigations into the evolution, structure and function of the cytokine receptors, and has permitted useful generalizations about the members of the families, and judicious extrapolations from one cytokine/receptor pair to another.
Until recently, the Class II cytokine receptor family (CRF2; also denoted HCRII, for helical cytokine receptor, Class II) included both subunits of the Type I interferon receptor (IFNAR-1 and IFNAR-2) and of the Type II IFN receptor (IFNGR-1 and IFNGR-2), tissue factor (TF), the ligand-binding chain of the IL-10 receptor (IL-10R1), and an “orphan” receptor, CRF2–4, later found to be the second subunit of the IL-10 receptor (IL-10R2). Improved genomic databases, sequence searching algorithms and investigator persistence in the face of low sequence homology permitted the discovery of five new members of the Class II cytokine receptor family (CRF2) in humans.
Parallel to the work on the receptors, new cytokines have been discovered by bioinformatic approaches, and by functional assays. Expression and co-expression of various CRF2 members and testing with putative ligands has permitted the pairing of ligands with receptors. However, an understanding of the biological/physiological roles and therapeutic potential of these ligands is still in its infancy.
The CRF2 receptors are listed in Table 1A and B. The corresponding Class II cytokines are organized by families in Table 2, and are diagrammatically paired with their receptors in Fig. 1. All the receptors except TF appear to function as heterodimers (see below).
Although this review will focus on the CRF2 family of receptors, it is worthwhile to introduce their ligands, which can be divided into several groups based on both structure and function (Table 2).
- (1)
The Type I IFNs [3], including the most recent human additions, IFN-κ [4] and IFN-ϵ [102] (also, IFN-τ in ruminants [5], and, in mice, limitin [6], [7], [8], [9]) were defined by their potent antiviral activity. However, even the IFN-αs and IFN-β stimulate an increasing list of activities which link innate and acquired immunity, including dendritic cell maturation, T-helper cell biasing, B cell differentiation, and NK activation [10]. The Type I IFNs all signal through IFNAR-1 and IFNAR-2, but their in vitro, physiological roles and therapeutic applications suggest that at least some of them are not biologically equivalent and interchangeable. While the functional repertoire of the “classical” Type I IFNs continues to expand, the functions of the newer members are only beginning to be explored.
- (2)
Type II IFN consists solely of IFN-γ [11], [12], [13]. Despite its classification as an interferon with antiviral activity, the genetic and physiological data point to a stronger role in protection against intracellular organisms and parasites such as mycobacteria and Listeria. IFN-γ affects diverse aspects of innate immunity, such as the activation of macrophages, and has strong effects on acquired responses, particularly in cell-mediated immunity, where it promotes the development of CD4+ Th1 cells and cytotoxic CD8+ T cells, while suppressing CD4+ Th2 cells. Studies with murine model tumor systems also demonstrate a role for IFN-γ (and T lymphocytes) in the natural suppression of tumor development [13]. IFN-γ utilizes the receptor subunits IFNGR-1 and IFNGR-2.
- (3)
A recently expanded group consists of IL-10 and its relatives, IL-19, IL-20, IL-22, IL-24 and IL-26 [14], [15], [16], [17]. These proteins are distantly related to one another (20–25% sequence identity), and have quite diverse functions, only some of which are currently known. They signal through different combinations of CRF2 proteins, with some sharing of receptor subunits (Table 1; Fig. 1). Viral homologues of IL-10, which serve as important virulence factors, have been found in large DNA viruses such as Epstein-Barr virus, cytomegalovirus and poxviruses [16], [17].
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The new IFN-λ or IL-28/29 family is comprised of three closely related proteins found together in the human genome [18], [19]. While these proteins have little sequence similarity to Type I IFNs, they share with Type I IFNs their antiviral activity, inducibility by viruses, and induction of at least several IFN-inducible proteins (MxA, 2′–5′ oligoadenylate synthetase, PKR), stimulation of transcription factors (ISGF-3) and intracellular kinases (Tyk2, Jak1). However, they utilize the receptor protein pair CRF2–12 (a.k.a. IFN-λR1 or IL-28Rα) and CRF2–4 (IL-10R2). A major question is whether the IFN-λs primarily play a back-up role to the Type I IFNs, or whether they have one or more undiscovered unique functions (see below).
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Finally, Factor VIIa, the ligand for tissue factor (TF) is truly an outlier, being dissimilar from the other CRF2-related cytokines in both structure and function [20]. It will not be further discussed in this review.
Several structure/function reviews have appeared for the best studied cytokine receptors, particularly those with crystal structures [21], [22]. In addition, the genetics, evolution and structure of the chromosome 21-encoded CRF2 receptors, particularly IFNAR, have been summarized [23].
This review will update and expand these, with the inclusion of the newly discovered CRF2 family members. After presenting an overview of the receptor family, we will focus on recent structure and function studies of ligand binding, demonstrating the pattern of receptor interactions that has emerged. These observations combined with homology modeling of these structurally conserved proteins provide a strong starting point for future structure/function studies of ligand binding and for an understanding of ligand specificity by the CRF2 receptors.
Section snippets
The Class II cytokine receptors (CRF2)
The CRF2 proteins are tripartite single-pass transmembrane proteins defined by structural similarities in the extracellular domain, which includes the ligand-binding residues [1], [2], [24]. The 200-amino-acid extracellular domain, more specifically denoted a cytokine receptor homology (CRH) domain, is composed of 2 tandem fibronectin Type III (FNIII) domains, a structural motif in the immunoglobulin fold superfamily (Fig. 2). We will refer to the amino-terminal FNIII domain, distal to the
Into the future
Structural (crystallographic or NMR) data or structure/function mutagenesis data on ligand–receptor complexes are only available for 4 of 12 CRF2 proteins. Nevertheless, mapping the receptor contact residues from crystal structures and from mutagenesis results onto the sequence alignments provides a fairly consistent picture of the use of various parts of the receptors in ligand binding (Fig. 3, Fig. 5).
As with several Class I receptors, many of the ligand binding interactions are dominated by
Acknowledgements
This study was supported in part by United States Public Health Services Grant RO1 AI51139 from the National Institute of Allergy and Infectious Diseases and by American Heart Association Grant AHA #0245131N to S.V.K.
References (102)
Haematopoietic receptors and helical cytokines
Immunol. Today
(1990)- et al.
Structural symmetry of the extracellular domain of the cytokine/growth hormone/prolactin receptor family and interferon receptors revealed by hydrophobic cluster analysis
FEBS Lett.
(1991) - et al.
Interferon-kappa, a novel Type I interferon expressed in human keratinocytes
J. Biol. Chem.
(2001) - et al.
Trophoblast interferons
Placenta
(1999) - et al.
T lymphocytes constitutively produce an interferonlike cytokine limitin characterized as a heat- and acid-stable and heparin-binding glycoprotein
Blood
(2003) Interferons alpha and beta as immune regulators—a new look
Immunity
(2001)- et al.
The roles of IFN gamma in protection against tumor development and cancer immunoediting
Cytokine Growth Factor Rev.
(2002) - et al.
The interleukin-10 family of cytokines
Trends Immunol.
(2002) The family of IL-10-related cytokines and their receptors: related, but to what extent?
Cytokine Growth Factor Rev.
(2002)- et al.
Structural basis for cytokine hormone-receptor recognition and receptor activation
Adv. Protein Chem.
(1998)
Other kinases can substitute for Jak2 in signal transduction by interferon-gamma
J. Biol. Chem.
Chimeric erythropoietin-interferon gamma receptors reveal differences in functional architecture of intracellular domains for signal transduction
J. Biol. Chem.
Soluble interferon-alpha receptor molecules are present in body fluids
FEBS Lett.
Cloning and characterization of soluble and transmembrane isoforms of a novel component of the murine Type I interferon receptor, IFNAR 2
J. Biol. Chem.
The soluble murine Type I interferon receptor Ifnar-2 is present in serum, is independently regulated, and has both agonistic and antagonistic properties
Blood
Differential responsiveness of a splice variant of the human Type I interferon receptor to interferons
J. Biol. Chem.
Cytokine signaling in 2002: new surprises in the Jak/Stat pathway
Cell
Seeing the light: preassembly and ligand-induced changes of the interferon gamma receptor complex in cells
Mol. Cell Proteomics
Caveolae and clathrin-coated vesicles: two possible internalization pathways for IFN-gamma and IFN-gamma receptor
Cytokine
Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex
Struct. Fold Des.
Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site
Immunity
The crystal structure of the extracellular domain of human tissue factor refined to 1.7 Å resolution
J. Mol. Biol.
The human Type I interferon receptor: NMR structure reveals the molecular basis of ligand binding
Structure
Mutational and structural analysis of the binding interface between Type I interferons and their receptor Ifnar2
J. Mol. Biol.
Identification of critical residues in bovine IFNAR-1 responsible for interferon binding
J. Biol. Chem.
The structure and activity of a monomeric interferon-gamma:alpha-chain receptor signaling complex
Structure
Bovine Type I interferon receptor protein BoIFNAR-1 has high-affinity and broad specificity for human Type I interferons
FEBS Lett.
Shared receptor components but distinct complexes for alpha and beta interferons
J. Mol. Biol.
Structural, functional and evolutionary implications of the three-dimensional crystal structure of murine interferon-β
Pharmacol. Ther.
Domains of interaction between alpha interferon and its receptor components
J. Mol. Biol.
New structural and functional aspects of the Type I interferon–receptor interaction revealed by comprehensive mutational analysis of the binding interface
J. Biol. Chem.
X-ray crystal structure of a small antagonist peptide bound to interleukin-1 receptor type 1
J. Biol. Chem.
Contributions of cloned Type I interferon receptor subunits to differential ligand binding
FEBS Lett.
Molecular cloning and expression of the human interferon-gamma receptor
Cell
Identification and sequence of an accessory factor required for activation of the human interferon gamma receptor
Cell
A novel member of the interferon receptor family complements functionality of the murine interferon gamma receptor in human cells
Cell
Genetic transfer of a functional human interferon-α receptor into a mouse cells: cloning and expression of its cDNA
Cell
The human interferon alpha/beta receptor: characterization and molecular cloning
Cell
Cloning and expression of a long form of the beta subunit of the interferon alpha beta receptor that is required for signaling
J. Biol. Chem.
Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2–4 and IL-22R
J. Biol. Chem.
Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes
J. Biol. Chem.
Interleukin 20: discovery, receptor identification, and role in epidermal function
Cell
Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2
J. Biol. Chem.
The evolution of the Type I interferons
J. Interferon Cytokine Res.
An interferon-like cytokine that preferentially influences B-lymphocyte precursors
Nat. Med.
A new IFN-like cytokine, limitin, modulates the immune response without influencing thymocyte development
J. Immunol.
Limitin: an interferon-like cytokine without myeloerythroid suppressive properties
J. Mol. Med.
The IFN gamma receptor: a paradigm for cytokine receptor signaling
Annu. Rev. Immunol.
The interferon receptors
Semin. Oncol.
Interleukin-10 and the interleukin-10 receptor
Annu. Rev. Immunol.
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