Leukocyte immunoglobulin-like receptors
Leukocyte immunoglobulin-like receptors (LIR) or CD85 have extracellular immunoglobulin domains. LIR modulates a variety of immune cells. LIR interacts with class I MHC molecules[1]. (PDB entry 1p7q). .
Cytokine receptors
TNF receptor superfamily
The extracellular domain of TNFR contains 2 to 6 cysteine-rich domains (CRD). The . The CRDs are involved in binding of TNF[2]. . Water molecules are shown as red spheres.
TRAIL-R2 is called DR5. (1d0g).
Colony-stimulating factor receptor
The via the conserved kinase DFG motif (colored in salmon) and its gatekeeper threonine residue (colored in magenta)[3].
The structure of the complex between M-CSF and its receptor shows that a . There are [4]. .
Type I cytokine receptors
(PDB code 1cn4).
(PDB code 3mzg). The interaction between PRLR and prolactin is strongly pH-dependent and is critically dependent on [5]. Water molecules are shown as red spheres. .
Type II cytokine receptors
Interferon receptors
All initiate signaling by binding to the same cell surface receptor composed of two subunits called and . The intracellular domains (ICDs) of IFNAR1 and IFNAR2 are associated with the Janus kinases (Jaks) Tyk2 and Jak1, respectively. Upon ligand binding by the IFNAR chains and formation of the signaling complex, these tyrosine kinases trans-phosphorylate and thereby activate each other. Subsequently, the activated Jaks phosphorylate STAT transcription factors, which translocate into the nucleus and activate the expression of hundreds of IFN-stimulated genes. To gain insight into how type I IFNs engage their receptor chains, how the receptor system is able to recognize the large number of different ligands, and how different IFN ligands can evoke different physiological activities, we determined the crystal structures of unliganded , the binary complex , and the ternary ligand-receptor complexes of and binding both receptor chains. A final theoretical ternary structure including was also created. These structures, in conjunction with biochemical and cellular experiments, reveal that the type I IFN receptor uses a mode of ligand interaction that is unique among cytokine receptors, but conserved between different IFNs. Furthermore, ligand discrimination occurs through distinct energetics of shared receptor contacts, and differential IFN signaling is mediated by specific ligand-receptor interface chemistries that lead to different ternary complex stabilities.
interacts primarily with the . Arg33(IFN) appears to be the for the interaction of the IFN ligand with IFNAR2. It forms an extensive hydrogen-bonding network with the main chain carbonyl oxygen atoms of Ile45(IFNAR2) and Glu50(IFNAR2) and the side chain of Thr44(IFNAR2). This residue is present in IFNa, IFNw, IFNb and IFNe. Two hydrophobic interaction clusters are part of the IFNa-IFNAR2 interface: the first one is formed between Leu15 and Met16 of the IFN molecule and Trp100 and Ile103 of IFNAR2; the second one comprises Leu26, Phe27, Leu30 and Val142 of the ligand and Met46, Leu52, Val80 and the methyl group of Thr44 of the receptor. Replacing reduces affinity by three orders of magnitude (the second most important residue for binding). This is surprising, as it is not engaged in any intimate contacts with IFNAR2 residues. One reason for its importance might be a .
Most of the residues involved in the IFNa2-IFNAR2 interaction are also found in the IFNw-IFNAR2 interface of the IFNw ternary complex.
A significant difference in the IFNAR2 interface between and IFNw is related to , which is replaced with Lys152 in . In the , this residue forms an with Glu149(IFN), but .
Because of the lower resolution of the IFNa ternary complex, we focused on the in our analysis of the IFN-IFNAR1 interface. In the , the only contains two hotspot residues we could experimentally confirm, and Phe238(IFNAR1). Substituting these residues by alanine reduces the affinity to all tested IFN ligands by more than 10-fold. On IFNw, mutation studies have shown that a charge-reversal mutation of Arg123 (Arg 120 on IFNa) leads to a total loss of activity.
Indeed, this residue forms a salt bridge with Asp132(IFNAR1) in addition to a hydrogen bond with Ser182(IFNAR1). Substitution of glutamate for Arg123(IFN) would lead to electrostatic repulsion with Asp132(IFNAR1).
The low affinity of IFNAR1 for the ligand appears to be functionally relevant, as weak binding to IFNAR1 is conserved between all alpha IFNs. Three amino acid substitutions on IFNa2 at positions His57, Glu58 and Ser61 to alanine or to Tyr, Asn, and Ser, respectively, confer tighter binding to IFNAR1, but leave the affinity to IFNAR2 essentially unaltered.
30% and 33% sequence identity with and IFNa2, respectively. in our ternary complex structure leads of side chains (Tyr92 and ) with the receptors, indicating that the IFNb ligand could be easily accommodated by the receptors in a position similar to IFNw and IFNa2. Furthermore, the shows that . As a result, Ala19(IFN), when mutated to tryptophan, promotes an increased binding affinity to IFNAR2, which is a result of the (as shown by double mutant cycle analysis).
One of the more controversial aspects of cytokine signaling is whether receptor binding is sufficient to generate activity, or if it has to be accompanied by structural perturbations. The type I interferon signaling complex is a rare example of a cytokine receptor complex were the structures of all the components making up the biologically active complex were determined to high resolution in both their free and bound forms. of the unbound NMR structure with the ternary complex structure of interferon shows a small expansion during complex formation.
Both IFNAR1 and IFNAR2, however, undergo significant domain movements upon binding. Using the D1 domain as anchor, a of IFNAR2 upon binding, on a scale of 6-12 Å, is observed (comparison of the unbound receptor (1n6u) with the binary IFNa2-IFNAR2 complex). The superimposition of the IFNa2-IFNAR2 binary complex with IFN-IFNAR2 in the ternary complexes of 6-9 Å, and even between the ternary IFNa and IFNw complexes a movement of 3-5 Å is observed. The D2 domain is engaged in crystal contacts in all three structures, and it remains an open question if the conformational changes in IFNAR2 are physiologically relevant. Still, these movements could change the proximity or orientation of the ICDs and associated Jaks within the cell.
The low-affinity receptor chain, IFNAR1, also upon ligand binding. When using D1 as anchor, D3 is moving inwards (toward the ligand) by ~15 Å. This would generate an even larger movement of the membrane-proximal SD4 domain and the transmembrane helix. The conformational changes in IFNAR1 are necessary to form the full spectrum of interactions with the IFN ligand, and to form a stable signaling complex that is able to instigate downstream signaling. In contrast to SD3, SD4 seems to be highly flexible (even more than D2 of IFNAR2). One might suggest that the conformational changes in IFNAR1 by itself will be responsible for a reduced binding affinity of IFNAR1 and may slow down the rate of ligand association to IFNAR1 directly from solution.
Classical MS pathology has been characterized by white matter plaques, shown in the image above, which are typically located in the subcortical or periventricular white matter, optic nerve sheaths, brain stem, and spinal cord. The lesions that occur in these regions are generally identified by perivascular infiltrates that contain clonally expanded (two ectodomains shown, 3qzw), as well as a smaller amount of (3t0e), (2ra4), and rare (4e96) and (2wq9). Pathologists disagree on whether there are different mechanisms for the inflammatory and degenerative components of MS, especially given that older patients have generally progressed further along with their degeneration. There are many proposed degeneration mechanisms including Wallerian degeneration secondary to demyelination, and axonal transection, damage from reactive oxygen species and nitric oxide, or energy failure from mitochondrial dysfunction. Many antigens have been investigated to determine whether they are the cause of autoreactivity (extracellular domain shown, 1tcr) in the hopes to determine a single culprit including: (MBP, 1bx2) with a peptide shown; (PLP, 2xpg) with peptide shown; (MOG, 3csp); oligodendroglia-specific enzyme transaldolase, and heat shock protein (2y1z).
Interesting discoveries have been made on possible inhibitors of myelin repair functions within the body, with an obvious application to MS treatment. The structure of the is a module implicated in central nervous system repair inhibition. The interactions of lingo-1 with receptors lead to neurite and axonal collapse. Lingo- 1 also regulates oligodendrocyte differentiation and myelination, thus leading to the suggestion that pharmacological modulation of Lingo-1 function could be a novel approach for nerve repair and remyelination therapies.
A protein growth factor that stimulates an antiviral defense is one of the only two known vertebrate structural genes that lacks introns.[7] Interferon-β is a relatively simple biological response modifier, with several . It consists of five , as well as multiple interconnecting . Helices A, B and D run , and helices C and E run to the other three helices, but to one another. Helix A consists of residues 6-23; Helix B consists of residues 49-65; Helix C consists of residues 77-91; Helix D consists of residues 112-131; and Helix E consists of residues 135-155.
Since a PDB reference does not exist for interferon-β interacting with interferon receptors 1 or 2, and a multitude of files exist on interacting with the receptor, a comparison to interferon-α will be made prior to demonstrating the types of bonding that occur between the interferon and its receptor. To see more information regarding interferons, please visit the Interferons site.
Interferon-α has a 31% sequence homology to interferon-β. It too has many with two : one between the , and the other between . It has seven , as compared to the five of interferon-β, and therefore has more The helices A, C, and F run to one another, and to B, E, and G which run to each other. does not run parallel or anti-parallel to either set, but rather runs at a 45-90 degree angle to them. Helix A consists of residues 10-12; Helix B of 40-43; Helix C of 53-68; Helix D of 70-75; Helix E of 78-100; Helix F of 109-132; and Helix G of 137-158.
Interferons-α and -β interact with a receptor at the cell surface.[8] This receptor has : an , with two disulfide bonds, a , with one disulfide bond, and a . The of the receptor have no secondary structure, allowing for some serious flexibility, leading to , which are all illustrated on the N-terminus region.[9]
Interferon-α to an interferon receptor mainly with helices C and G. There are many , shown in ball-and-stick, within 4 angstroms of one another. These residues could form many , with hydrogen bonds illustrated in white dotted lines. Given that interferon-α does not undergo many structural changes upon binding to interferon receptor II, Quadt-Akabayov et al. have concluded that the binding mechanism is similar to that of a lock and key. While interferon-α and -β bind to the same receptors as one another, the affinities with which they bind to IFNAR1 and IFNAR2 differ. While the binding to IFNAR2 is stronger for both in comparison to IFNAR1, interferon-β has a much stronger affinity for IFNAR1 than interferon-α.
Interleukin receptors
Interleukin-20 receptor:
Chemokine receptors, two of which acting as binding proteins for HIV (CXCR4 and CCR5). They are G protein-coupled receptors
T-cell receptors
See also:
