User:Chengfeng Ren/IFN beta 1a

From Proteopedia

IFN Categories and IFNβ-1a sources

Interferons (IFNs) are a family of helical cytokines that mediate antiviral, antiproliferative, and immune modulatory activities in response to biological and chemical stimuli. Two types of IFN are recognized on the basis of their physical and biological properties; type I, which contains the monomeric IFNs-α,-β,-τ, and -ω, and type II, the only member of which is the dimeric IFN-γ. Representatives of all type I and type II IFNs are found in humans, except for IFN-τ, which is found only in ruminant ungulates. There are 12 different human IFNs-α;each one comprising a different subtype,although 14 different genes have been identified, whereas human IFN-β, IFN-ω, and IFN-γare encoded by single genes[1].

Interferon-β has two subtyes, interferon-β-1a and interferon-β-1b. Interferon-β-1a is naturally expressed in numerous cell types in human, including fibroblasts, endothelial cells, epithelial cells and various leukocytes, however,Interferon-β-1b is produced in modified E. coli.

Here is a jpg clearly illustrating IFNs categories.

Structure info. of IFNβ-1a

IFNβ-1a consisting of 166 amino acids, around 20KDa. It has 5 helixs. There are several ,such as Phe-70, Phe-154, Trp-79, and Trp-143, that are involved in interactions with each other that stabilize the core of the molecule. In addition, residues of the core form several such as between Gln-10 and Gln-94 and between Ser-118 and Thr-58. Additional interactions that appear to stabilize the loop are between Tyr-132 OH and Asp-34 O and between Arg-147 N and Leu-24 O. Cys-31 forms a with Cys-141 of and plays an important role in the stabilization of protein structure. Interferon-β-1a tends to aggregate and form . A zinc ion is observed to exist at the . It is coordinated in a tetrahedral manner by His-121 of molecule A and His-93 and His-97 of molecule B. A water molecule occupies the fourth coordination site. A network of formed between His-121 and Glu-43 (molecule A) and between His-97 and Gln-94 (molecule B) appears to assist in the stabilization of the zinc-binding site.

chain A

IFNβ-1a biological activity and therapeutic effects

IFNβ-1a as well as other family of IFNs has a variety of biological activities, inluding antiviral, antiproliferative, and immune modulatory activities in response to biological and chemical stimuli[2].

IFNβ-1a is mainly used to treat relapsing forms of multiple sclerosis(MS). MS is a life-long disease that affects your nervous system by destroying the protective covering (myelin) that surrounds your nerve fibers. The commercial available drug format is Avonex.(Please refer to the drug guide before using it)

Mechanism of action for IFNβ-1a

The IFNβreceptor, signaling cascade and gene regulation

The IFNβreceptor is composed of 2 required chains—a signaling chain, , and a binding chain, . Both IFNAR1 and IFNAR2 are constitutively expressed on the surface of virtually all cells. IFNβcan bind to IFNAR2 alone, but can bind to IFNAR1 only in the presence of IFNAR2. The strength of IFNβbinding to its receptor is much higher when both subunits are present. Knockout experiments indicate that both IFNAR1 and IFNAR2 are required for IFNβ activity, but it remains uncertain whether there are auxiliary receptors or alternative receptor/ signaling complexes in some cell types. The current view of events leading to IFNβbiological activity is as follows: 1) IFN binds to the extracellular domain of IFNAR2. 2) IFNAR1 then engages with the IFNβ–IFNAR2 complex, forming the high-affinity receptor–ligand complex and allowing the intracellular domains of the two receptor chains and associated proteins to interact. 3) This interaction, which includes JAK1 (associated with IFNAR2) and Tyk2 (associated with IFNAR1), results in a cascade of phosphorylation events that leads to activation of STATS. 4) Activated STATS form a complex with other cytoplasmic proteins, which then translocate into the nucleus to bind to Interferon Sensitive Response Elements (ISRE), transcriptional control regions which are upstream of many IFN regulated genes. 5) This ISRE binding results in transcriptional regulation (both induction and inhibition) of >1000 genes. Thus, IFN regulates expression of a myriad of genes. While the function of some of these genes is clear (e.g. the antiviral product MxA), the specific transcripts mediating therapeutic benefit of IFNβin MS are unknown. This is, in part, due to the complexity and heterogeneity of MS, but also because IFNβis an agonist that can induce the expression not only of ISRE regulated genes, but through newly expressed transcription factors, can induce or inhibit subsequent waves of gene expression. In addition, some IFNβregulated proteins, which include cytokines and chemokines, can alter the level or function of particular cell populations. The resulting multifaceted biological response is in contrast to therapies such as monoclonal antibodies that have a much more specific molecular target[2-9].

Reference

[1] R. Arduini, K. Strauch, L. Rukel etal.Characterization of a soluble ternary complex formed between human interferon-b-1a and its receptor chainsProtein Science (1999),8:1867–1877

[2] T. Taniguchi, A. Takaoka, The interferon-alpha/beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors, Curr. Opin. Immunol. 14 (1) (Feb 2002) 111–116.

[3] K. Kasama, J. Utsumi, E. Matsuo-Ogawa, T. Nagahata, Y. Kagawa, S. Yamazaki, et al., Pharmacokinetics and biologic activities of human native and asialointerferon-beta s, J. Interferon Cytokine Res. 15 (5) (May 1995) 407–415.

[4] L. Runkel, W. Meier, R.B. Pepinsky, M. Karpusas, A. Whitty, K. Kimball, et al., Structural and functional differences between glycosylated and non-glycosylated forms of human interferon-beta (IFN-beta), Pharm. Res. 15 (4) (Apr 1998) 641–649.

[5] R.M. Arduini, K.L. Strauch, L.A. Runkel, M.M. Carlson, X. Hronowski, S.F. Foley, et al., Characterization of a soluble ternary complex formed between human interferon-beta-1a and its receptor chains, Protein Sci. 8 (9) (Sep 1999) 1867–1877.

[6] G. Uze, G. Schreiber, J. Piehler, S. Pellegrini, The receptor of the type I interferon family, Curr. Top. Microbiol. Immunol. 316 (2007) 71–95.

[7] C.M. Cleary, R.J. Donnelly, J. Soh, T.M. Mariano, S. Pestka, Knockout and reconstitution of a functional human type I interferon receptor complex, J. Biol. Chem. 269 (29) (Jul 22 1994) 18747–18749.

[8] J. Kumaran, O.R. Colamonici, E.N. Fish, Structure–function study of the extracellular domain of the human type I interferon receptor (IFNAR)-1 subunit, J. Interferon Cytokine Res. 20 (5) (May 2000) 479–485.

[9] J. Ghislain, G. Sussman, S. Goelz, L.E. Ling, E.N. Fish, Configuration of the interferon-alpha/beta receptor complex determines the context of the biological response, J. Biol. Chem. 270 (37) (Sep 15 1995) 21785–21792.