Homology model of human interferon‐α8 and its receptor complex

Abstract

Human interferond (HuIFNa8), a type I interferon (IFN), is a cytokine belonging to the hematopoietic superfamily that includes human growth hormone (HGH). Recent data identified two human type I IFN receptor components. One component (p40) was purified from human urine by its ability to bind to immobilized type I IFN. A second receptor component (IFNAR), consisting of two cytokine receptor-like domains (D200 and D200'), was identified by expression cloning. Murine cells transfected with a gene encoding this protein were able to produce an antiviral response to human IFNa8. Both of these receptor proteins have been identified as members of the immunoglobulin superfamily of which H G H receptor is a member. The cytokine receptor-like structural motifs present in p40 and IFNAR were modeled based on the HGH receptor X-ray structure. Models of the complexes of HuIFNa8 with the receptor subunits were built by superpositioning the conserved C a backbone of the HuIFNa8 and receptor subunit models with HGH and its receptor complex. The HuIFNa8 model was constructed from the Ca coordinates of murine interferon-p crystal structure. Electrostatic potentials and hydrophobic interactions appear to favor the model of HuIFNa8 interacting with p40 at site 1 and the D200' domain of IFNAR at site 2 because there are regions of complementary electrostatic potential and hydrophobic interactions at both of the proposed binding interfaces. Some of the predicted receptor binding residues within HuIFNa8 correspond to functionally important residues determined previously for human IFNal, IFNa2, and IFNa4 subtypes by site-directed mutagenesis studies. The models predict regions of interaction between HuIFNa8 and each of the receptor proteins, and provide insights into interactions between other type I IFNs (IFN-a subtypes and IFN-p) and their respective receptor components.

Reduced interferon (IFN)-α conditioned by IFNA2 (−173) and IFNA8 (−884) haplotypes is associated with enhanced susceptibility to severe malarial anemia and longitudinal all-cause mortality

“…These results, along with the relatively similar risks associated with susceptibility to SMA for the IFNA8 TA genotype (OR=2.80) and the −173T/−884A (TA) haplotype (OR=3.98), and their comparable reductions in circulating IFN-α, suggests that it is actually variation at IFNA8 −884 that is driving the genetic-based relationship and consequent changes in IFN-α. These results are consistent with previous studies showing that the IFNA8 subtype is one of the most important type 1 interferon subtypes for regulating potent IFN-α production (Foster et al 1996; Garcia et al 2007; Izaguirre et al 2003; Seto et al 1995). …”

“…However, due to post-translational modifications, there are more than 22 IFN-α subtypes differing by one or two amino acids (Bekisz et al 2004; Song et al 2006). Several in vitro studies showed that these subtypes vary considerably in their ability to produce IFN-α in response to viruses and other stimuli (Izaguirre et al 2003; Seto et al 1995). …”

“…Among the IFN-α subtypes, IFNA8 is one of the highest producers of IFN-α and possesses potent antiviral activity (Foster et al 1996; Garcia et al 2007; Izaguirre et al 2003; Seto et al 1995). However, IFNA8 has not been investigated in the context of malaria.…”

Conformation and dynamics of biopharmaceuticals: Transition of mass spectrometry-based tools from academe to industry

“…Importantly, increased fluctuation within the receptor-binding interface region of human growth hormone (hGH) was recently linked directly to the increased free energy of the protein-receptor binding (60), which belongs to the same hematopoietic super-family that includes type I interferons (61). The two proteins (hGH and IFN) are highly homologous, so much so that hGH was used in earlier homology modeling of IFN and INF/IFNARs binding (61, 62).…”

“…The two proteins (hGH and IFN) are highly homologous, so much so that hGH was used in earlier homology modeling of IFN and INF/IFNARs binding (61, 62). Helix 1 of hGH is noticeably more stable compared to its cousin helix A of IFN; however, introducing a structure-destabilizing mutation in helix 1 leads to a noticeable increase in the receptor binding affinity (60).…”