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Introduction

Ciliary neurotrophic factor, 1cnt

Human Ciliary Neurotrophic Factor (CNTF) is a roughly 23 kDa protein consisting of a single polypeptide chain of 200 amino acid residues. It is a nerve growth factor belonging to the Interleukin-6 (IL-6) family of neuropoietic cytokines. Other members of this family include leukemia inhibitory factor (LIF), IL-6, IL-11, oncostatin M, cardiotropin 1 (CT-1) and cardiotrophin-like cytokine (CLC) ^[1].

spinqualitylabelsall models Dimeric structure of CNTF in 2.4 Å resolution Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Receptor for CNTF and the biological role of CNTF Binding of CNTF to the high affinity receptor complexes CNTFRα/gp130/LIFRβ and to the low affinity receptor complex IL-6R/gp130/LIFRβ (modified from [1] [2]) CNTF exerts its biological function by binding into a tripartite receptor complex consisting of a specific CNTF receptor subunit α (CNTFRα) linked to the cell membrane with a glycosyl-phosphatidylinositol linkage, and two signal-transducing transmembrane subunits LIF receptor beta (LIFRβ) and gp130. Binding of a hCNTF dimer to CNTFRα is the absolute first requirement to initiate a signal transduction cascade, which ultimately results in the enhanced transcription of genes encoding e.g. acute phase plasma proteins, and suppressors of cytokine signaling. CNTFRα has been observed to exist also as a soluble receptor (sCNTFRα) [3], attributed to a phospholipase C-mediated cleavage [4]. Additionally, hCNTF has been observed to be able to bind both to membrane-bound and soluble human Interleukin-6 receptor (IL-6R) and use as a substitute it to form the receptor complex necessary for signal transduction [5] [6]. These observations are considered to offer explanation as to why cells expressing LIFRβ and gp130 but not CNTFRα, are nonetheless responsive to CNTF. CNTF's known biological functions involve affecting the growth, differentiation, survival and repair of various types of neurons and glial cells in both the central and peripheral nervous systems [7] [6]; evidence also suggests CNTF to be expressed in other tissues, such as adipocytes and hepatocytes among others [7] [6]. As the transcription of CNTF mRNA and CNTF distribution have been noticed to be altered upon neural injury, it has been suggested, that CNTF is not an absolute requirement for neural development, but in fact mainly acts in response to neural injuries and stresses . Furthermore, mice homozygous for an inactived CNTF gene have been observed to develop normally, and to display losses in motor neurons only later during adulthood. Although humans homozygous for an inactivated CNTF gene caused by a mutation have not been observed to suffer from major neurological abnormalities [1], this has been linked with early onset of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) [6]. However, mice that have a CNTFRα knock-out die already during the perinatal stage and exhibit severe motor neuron deficits [7], suggesting that CNTFRα might have a second ligand. Disease and Clinical applications A frameshift mutation in exon 2 of the CNTF gene affecting some 2-3 % of the population [8] causes earlier onset of the disease and quicker declination of motor neuron function in MS patients [9]. MS patients with functional CNTF show 1,7-fold increase of CNTF mRNA expression in the cortex, suggesting CNTF secretion as an innate response to progressing neuronal damage [10]. While not directly linked to disease, CNTF has been shown to inhibit the secretion of vascular endothelial growth factor (VEGF). VEGF, in turn, is upregulated in many diseases of the retina, causing increased angiogenesis. Thus CNTF-induced downregulation alleviates the symptoms of many ocular diseases [2]. It has been proposed that treatment with CNTF could counteract vision loss caused by age-related macular degeneration, retinitis pigmentosa and retinitis pigmentosa linked to Usher syndrome. In these cases the alleviating effect is produced by CNTF inducing regeneration of outer segments of cone cells in the retina [11]. Using encapsulated cells transfected with the human CNTF gene has been studied as a delivery method in clinical studies[12], [13]. As CNTF has also been shown to affect energy balance, it also has potential clinical applications in the prevention and treatment of obesity and type II diabetes [7] [14]. Structure Like with many other cytokines, the tertiary structure of CNTF consists of four anti-parallel α-helices (Arg13–His41), (Glu69–Val96), (Phe105–Leu129) and (Phe152–Ser180), where helices A-B and C-D are connected by two cross-over loops and helices B-C by one short loop. A partial crystal structure of a truncated form of hCNTF (2-187) is displayed here [15]. The CNTFRα-binding surface epitope of CNTF was studied with random mutagenesis and identified to consist of residues Arg25, Arg28, Gln63, Trp64, Gln74, Asp175 and Arg177. These residues are located in helix A, the loop between helices A-B, helix B and helix D, and are [16]. In addition, the LIFR-binding epitope of CNTF was identified to consist of Glu36-Met56, Leu91-Ile109 and Gly147-Leu162 [17]. The ability of hCNTF to bind both to CNTFRα and IL-6R has been mapped to residue Gln63 [5]. The dimeric structure of CNTF is attributed to the properties of hydrophobic (Leu91, Leu113, Leu114, Ala117, Tyr121, Ile128), polar (Gln95) and charged residues (Arg81, His84, Glu92, His106, His110, Glu124, Glu125) in the B and C helices of monomeric CNTF. These interface sites are highly conserved among species, except for Gln95. In the dimeric structure, , forming hydrogen bonds to His84 and Tyr121 of each monomer[15].

Additional Resources

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References

1. ↑ ^{1.0 1.1 1.2} Wen R, Tao W, Li Y, Sieving PA. CNTF and retina. Prog Retin Eye Res. 2012 Mar;31(2):136-51. doi: 10.1016/j.preteyeres.2011.11.005., Epub 2011 Dec 10. PMID:22182585 doi:http://dx.doi.org/10.1016/j.preteyeres.2011.11.005
2. ↑ ^{2.0 2.1} Li R, Wen R, Banzon T, Maminishkis A, Miller SS. CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium. PLoS One. 2011;6(9):e23148. doi: 10.1371/journal.pone.0023148. Epub 2011 Sep 2. PMID:21912637 doi:http://dx.doi.org/10.1371/journal.pone.0023148
3. ↑ Panayotatos N, Everdeen D, Liten A, Somogyi R, Acheson A. Recombinant human CNTF receptor alpha: production, binding stoichiometry, and characterization of its activity as a diffusible factor. Biochemistry. 1994 May 17;33(19):5813-8. PMID:8180210
4. ↑ Davis S, Aldrich TH, Ip NY, Stahl N, Scherer S, Farruggella T, DiStefano PS, Curtis R, Panayotatos N, Gascan H, et al.. Released form of CNTF receptor alpha component as a soluble mediator of CNTF responses. Science. 1993 Mar 19;259(5102):1736-9. PMID:7681218
5. ↑ ^{5.0 5.1} Schuster B, Kovaleva M, Sun Y, Regenhard P, Matthews V, Grotzinger J, Rose-John S, Kallen KJ. Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF. J Biol Chem. 2003 Mar 14;278(11):9528-35. PMID:12643274
6. ↑ ^{6.0 6.1 6.2 6.3} Cognet I, Guilhot F, Chevalier S, Guay-Giroux A, Bert A, Elson GC, Gascan H, Gauchat JF. Expression of biologically active mouse ciliary neutrophic factor (CNTF) and soluble CNTFRalpha in Escherichia coli and characterization of their functional specificities. Eur Cytokine Netw. 2004 Jul-Sep;15(3):255-62. PMID:15542451
7. ↑ ^{7.0 7.1 7.2 7.3} Sleeman MW, Anderson KD, Lambert PD, Yancopoulos GD and Wiegand SJ. "The ciliary neurotrophic factor and its receptor, CNTFRα". Pharm Acta Helv 74: 265-272 (2000). http://dx.doi.org/10.1016/S0165-7208(00)80028-8
8. ↑ Takahashi R, Yokoji H, Misawa H, Hayashi M, Hu J, Deguchi T. A null mutation in the human CNTF gene is not causally related to neurological diseases. Nat Genet. 1994 May;7(1):79-84. PMID:8075647 doi:http://dx.doi.org/10.1038/ng0594-79
9. ↑ Giess R, Maurer M, Linker R, Gold R, Warmuth-Metz M, Toyka KV, Sendtner M, Rieckmann P. Association of a null mutation in the CNTF gene with early onset of multiple sclerosis. Arch Neurol. 2002 Mar;59(3):407-9. PMID:11890844
10. ↑ Dutta R, McDonough J, Chang A, Swamy L, Siu A, Kidd GJ, Rudick R, Mirnics K, Trapp BD. Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients. Brain. 2007 Oct;130(Pt 10):2566-76. PMID:17898009 doi:http://dx.doi.org/10.1093/brain/awm206
11. ↑ Li Y, Tao W, Luo L, Huang D, Kauper K, Stabila P, Lavail MM, Laties AM, Wen R. CNTF induces regeneration of cone outer segments in a rat model of retinal degeneration. PLoS One. 2010 Mar 2;5(3):e9495. doi: 10.1371/journal.pone.0009495. PMID:20209167 doi:http://dx.doi.org/10.1371/journal.pone.0009495
12. ↑ Sieving PA, Caruso RC, Tao W, Coleman HR, Thompson DJ, Fullmer KR, Bush RA. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3896-901. Epub 2006 Feb 27. PMID:16505355 doi:http://dx.doi.org/10.1073/pnas.0600236103
13. ↑ Talcott KE, Ratnam K, Sundquist SM, Lucero AS, Lujan BJ, Tao W, Porco TC, Roorda A, Duncan JL. Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment. Invest Ophthalmol Vis Sci. 2011 Apr 6;52(5):2219-26. doi: 10.1167/iovs.10-6479. PMID:21087953 doi:http://dx.doi.org/10.1167/iovs.10-6479
14. ↑ Ettinger MP, Littlejohn TW, Schwartz SL, Weiss SR, McIlwain HH, Heymsfield SB, Bray GA, Roberts WG, Heyman ER, Stambler N, Heshka S, Vicary C, Guler HP. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. JAMA. 2003 Apr 9;289(14):1826-32. PMID:12684362 doi:http://dx.doi.org/10.1001/jama.289.14.1826
15. ↑ ^{15.0 15.1} McDonald NQ, Panayotatos N, Hendrickson WA. Crystal structure of dimeric human ciliary neurotrophic factor determined by MAD phasing. EMBO J. 1995 Jun 15;14(12):2689-99. PMID:7796798
16. ↑ Panayotatos N, Radziejewska E, Acheson A, Somogyi R, Thadani A, Hendrickson WA, McDonald NQ. Localization of functional receptor epitopes on the structure of ciliary neurotrophic factor indicates a conserved, function-related epitope topography among helical cytokines. J Biol Chem. 1995 Jun 9;270(23):14007-14. PMID:7539796
17. ↑ Kallen KJ, Grotzinger J, Lelievre E, Vollmer P, Aasland D, Renne C, Mullberg J, Myer zum Buschenfelde KH, Gascan H, Rose-John S. Receptor recognition sites of cytokines are organized as exchangeable modules. Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6. J Biol Chem. 1999 Apr 23;274(17):11859-67. PMID:10207005