User:Chengfeng Ren/IFN beta 1a: Difference between revisions

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'''~~Content~~

'''

==~~1.aaa==~~

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=='''IFN Categories and IFNβ-1a sources'''==

<~~Structure load~~='~~1a1u~~' ~~size~~='~~500~~' ~~frame~~='~~true~~' ~~align~~='~~right~~' ~~caption~~='~~IFN awesome~~' scene='~~IFN rocks~~' />

'''Interferons''' (IFNs) are a family of helical cytokines that mediate

<scene name='56/566503/~~Scene_one~~/1'>~~IFN turning around around~~</scene>

antiviral, antiproliferative, and immune modulatory activities in

<scene name='56/~~566503~~/~~Fin_scene_1~~/1'>~~IFN showing polar~~/~~nonpolar section~~</scene>

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.

[[Image:IFN categories.jpg]]

=='''Structure info. of IFNβ-1a'''==

IFNβ-1a consisting of 166 amino acids, around 20KDa. It has 5 helixs. There are several <scene name='56/566503/Important_hydrophobic_residues/2'>hydrophobic residues</scene>,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 <scene name='56/566503/H-bonding/3'>hydrogen bonding</scene> such as between Gln-10 and Gln-94 and between Ser-118 and Thr-58. Additional interactions that appear to stabilize the loop are <scene name='56/566503/H-bonding/2'>hydrogen bonds</scene> between Tyr-132 OH and Asp-34 O and between Arg-147 N and Leu-24 O. Cys-31 forms a <scene name='56/566503/Disulfide_bridge/1'>disulfide bridge</scene> with Cys-141 of and plays an important role in the stabilization of protein structure.

Interferon-β-1a tends to aggregate and form <scene name='56/566503/Interferon_dimer/1'>dimer</scene>.

A zinc ion is observed to exist at the <scene name='56/566503/Interferon_dimer/2'>interface between molecules A and B</scene>. 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 <scene name='56/566503/H-bonding_in_interferon_dimer/1'>hydrogen bonds</scene> 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.

<scene name='56/566498/Interferon_beta_1a/1'>Interferon beta 1a</scene>

<scene name='56/566503/Momomer_for_further_work/1'>monomer for current work</scene> 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 [http://http://www.avonex.com/ 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,<scene name='56/566498/Human_ifnar1/1'>IFNAR1</scene> , and a binding chain, <scene name='56/566498/Ifnar2/1'>IFNAR2</scene>. 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 chains''Protein 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.

@@ Line 1: / Line 1: @@
-'''Content
+<Structure load='Insert PDB code or filename here' size='350' frame='true' align='right' caption='A zinc is in the interface between molecules A and B' scene='56/566503/Interferon_dimer/2' />
-'''
-==1.aaa==
-==2.bbbb==
-==3.ddd==
+=='''IFN Categories and IFNβ-1a sources'''==
-<Structure load='1a1u' size='500' frame='true' align='right' caption='IFN awesome' scene='IFN rocks' />
+'''Interferons''' (IFNs) are a family of helical cytokines that mediate
-<scene name='56/566503/Scene_one/1'>IFN turning around around</scene>
+antiviral, antiproliferative, and immune modulatory activities in
-<scene name='56/566503/Fin_scene_1/1'>IFN showing polar/nonpolar section</scene>
+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.
+[[Image:IFN categories.jpg]]
+=='''Structure info. of IFNβ-1a'''==
+IFNβ-1a consisting of 166 amino acids, around 20KDa. It has 5 helixs. There are several <scene name='56/566503/Important_hydrophobic_residues/2'>hydrophobic residues</scene>,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 <scene name='56/566503/H-bonding/3'>hydrogen bonding</scene> such as between Gln-10 and Gln-94 and between Ser-118 and Thr-58. Additional interactions that appear to stabilize the loop are <scene name='56/566503/H-bonding/2'>hydrogen bonds</scene> between Tyr-132 OH and Asp-34 O and between Arg-147 N and Leu-24 O. Cys-31 forms a <scene name='56/566503/Disulfide_bridge/1'>disulfide bridge</scene> with Cys-141 of and plays an important role in the stabilization of protein structure.
+Interferon-β-1a tends to aggregate and form <scene name='56/566503/Interferon_dimer/1'>dimer</scene>.
+A zinc ion is observed to exist at the <scene name='56/566503/Interferon_dimer/2'>interface between molecules A and B</scene>. 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 <scene name='56/566503/H-bonding_in_interferon_dimer/1'>hydrogen bonds</scene> 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.
+<scene name='56/566498/Interferon_beta_1a/1'>Interferon beta 1a</scene>
+<scene name='56/566503/Momomer_for_further_work/1'>monomer for current work</scene> 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 [http://http://www.avonex.com/ 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,<scene name='56/566498/Human_ifnar1/1'>IFNAR1</scene> , and a binding chain, <scene name='56/566498/Ifnar2/1'>IFNAR2</scene>. 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 chains''Protein 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.
+(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)
+–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)
+–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.