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DescriptionDescription
The Glycogen Synthase Kinase 3 beta- GSK-3β, also known as the tau-protein-kinase I, is a serine protein kinase that participates in many different pathways regulating critical cellular functions as the structure, the gene expression, the mobility, and the apoptosis,[1]. GSK-3 phosphorylates a large number of substrates and is himself regulated by phosphorylation,[2].
GSK-3 is implicated in several diseases like Alzheimer’s disease, diabetes, mood disorders and cancer,[3]. In the Alzheimer’s disease, it is thought to be tied to the process of the hyperphosphorylation of tau proteins,[4] which leads to the formation of neurofibrillary tangles and to the build up of Amyloid-β (Aβ) deposits. Dephosphorylated tau binds normally to microtubules, one of the major components of the neuronal cytoskeleton that contributes to the proper function of neurons.
Considering the roles plaid by GSK3 in promoting both pathological features of Alzheimer disease, GSK3-inhibitors may act positively in the therapy of Alzheimer’s patients. But due to the importance of its role in numerous cellular functions, it is important to develop inhibitors that do not affect or suppress its primary activity,[5].
There are two isoforms of GSK-3: GSK3α and GSK3β,[2]. Our concern focuses on GSK3β.The two main mechanisms that affect the activity of the kinase are its inhibition by phosphorylation of serine-9 and its activity enhancement by phosphorylation of tyrosine-216,[3].
GSK-3β can phosphorylate tau on Ser-199, Thr-231, Ser-396, Ser-400, Ser-404, and Ser-413 in vivo and in vitro,[6] [7].
ActivityActivity
Since GSK-3 is constitutively active in most cell types, regulation of substrate phosphorylation occurs either by inactivation of GSK-3 or by changing substrate accessibility or recognition. The structure indicates the preference of GSK-3 for primed, pre-phosphorylated substrates. There are numerous putative GSK-3 substrates with roles in a wide spectrum of cellular processes including: glycogen metabolism, transcription, translation, cytoskeletal regulation, intracellular vesicular transport, cell cycle progression, circadian rhythm regulation and apoptosis,[7]
The EC code indicates that GSK-3β belongs to two different classes,[8]:
- Enzyme classe 1 with E.C.2.7.11.1 it's a non-specific serine/threonine protein kinase
which performs this reaction: ATP + a Protein = ADP + a Phosphoprotein
- Enzyme classe 2 with E.C.2.7.11.26 it's a [Tau protein] kinase
which performs this second reaction: ATP + [tau protein] = ADP + [tau protein] phosphate
StructureStructure
,[9]The Ramachandran plot of 1j1c shows that the binary complex has β-sheets and α-helices. For further details on the diagram, please follow the link.
This protein is composed by two subunits A (green) and B (blue) linked by 12 hydrogen bonds in order to stabilize the molecule. But only four are shown on the 3D picture (with red dashed lines) with their engaged: Ser-66, Ser-215,Tyr-216, Arg-220, Gly-230, Asp-260, Gly-262, Val-263, Tyr-288, Ser-715,Tyr-716, Arg-720, Asp-760,Val-763, Asp-764, Tyr-788 and Glu-790. The full list of interactions between these amino-acids is shown in this page.
This structure also possesses as well as (Adenosine DiPhosphate). Arg-141 is one of the key residues for by GSK3,[1]. You can find more details about this recognition in the following two links, for the ADP, for Mg2+.
The engaged in the catalytic site of the protein are Asp-181, Lys-183, Gln-185, Asn-186 and Ser-219. They are polar and localised in 3' end.
This enzyme is activated by phosphorylation on and inactivated by phosphorylation on Ser-9 (not shown here because the solved structure starts at residue 35). But the phosphorylation on Tyr-216 is not mandatory for the activity,[10].
This structure has 2 domains according to the CATH structural classification:
External RessourcesExternal Ressources
ReferencesReferences
- ↑ 1.0 1.1 "Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 beta." Aoki, M., Yokota, T., Sugiura, I., Sasaki, C., Hasegawa, T., Okumura, C., Ishiguro, K., Kohno, T., Sugio, S., Matsuzaki, T. Journal: (2004) Acta Crystallogr.,Sect.D60: 439-446
- ↑ 2.0 2.1 "Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics." Richard S. Jope,* Christopher J. Yuskaitis, and Eléonore Beurel Neurochem Res. 2007; 32(4-5): 577-595.
- ↑ 3.0 3.1 "GSK-3β Directly Phosphorylates and Activates MARK2/PAR-1." Shinichi Kosuga1, Etsu Tashiro1, Toshifumi Kajioka, Mayumi Ueki, Yoshifumi Shimizu and Masaya Imoto2 Journal of biological Chemistry 2005
- ↑ "Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors".Bertrand JA, Thieffine S, Vulpetti A, Cristiani C, Valsasina B, Knapp S, Kalisz HM, Flocco M (October 2003). J. Mol. Biol. 333 (2): 393-407. doi:10.1016/j.jmb.2003.08.031. PMID 14529625.
- ↑ "GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals.". 5 Hu S (Feb 2009).Neurobiol Dis. 33 (2): 193-206. doi:10.1016/j.nbd.2008.10.007. PMID 19038340.
- ↑ "Structure and Pathology of Tau Protein in Alzheimer Disease." Michala Kolarova,1,2 Francisco García-Sierra,3 Ales Bartos,1,4 Jan Ricny,1 and Daniela Ripova1, International Journal of Alzheimer's Disease Volume 2012 (2012), Article ID 731526, 13 pages doi:10.1155/2012/731526
- ↑ 7.0 7.1 " GSK-3: tricks of the trade for a multi-tasking kinase". Doble BW, Woodgett JR.J Cell Sci. 2003 Apr 1;116(Pt 7):1175-86.
- ↑ http://www.ebi.ac.uk/pdbsum/1j1c
- ↑ http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1j1c&template=procheck_summary.html
- ↑ "Crystal Structure of Glycogen Synthase Kinase 3β: Structural Basis for Phosphate-Primed Substrate Specificity and Autoinhibition" Rana Dajani, Elizabeth Fraser, S. Mark Roe, Neville Young, Valerie Good, Trevor C. Dale and Laurence H. Pearl1; Cell, Vol. 105, 721–732, June 15, 2001, Copyright 2001 by Cell Press