Sandbox Reserved 708: Difference between revisions

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 structure, gene expression, mobility, and apoptosis,<ref>1 "Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 beta."

Journal: (2004) Acta Crystallogr.,Sect.D60: 439-446</ref>. GSK-3 phosphorylates a large number of substrates and is himself regulated by phosphorylation,<ref>  "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.</ref>.

GSK-3 is implicated in several diseases like Alzheimer’s disease, diabetes, mood disorders and cancer,<ref> "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</ref>. In the Alzheimer’s disease, it is thought to be tied to the process of the hyperphosphorylation of tau proteins,<ref> "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.</ref> 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,<ref> "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.</ref>.

There are two isoforms of GSK-3: GSK3α and GSK3β,<ref> "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.  </ref>. Our concern focuses on GSK3 two 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,<ref> "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</ref>.

GSK-3β can phosphorylate tau on Ser-199, Thr-231, Ser-396, Ser-400, Ser-404, and Ser-413 in vivo and in vitro,<ref> "Structure and Pathology of Tau Protein in Alzheimer Disease."

doi:10.1155/2012/731526</ref> <ref>" 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.</ref>

{{STRUCTURE_1j1c| PDB=1j1c | SCENE= Sandbox_Reserved_708/Complete_binary_complex/3 }}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 has provided insight into 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,<ref> " 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.</ref>.

This enzyme is activated by phosphorylation on <scene name='Sandbox_Reserved_708/Tyr-216_phosphorylation/3'>Tyr-216</scene> and inactivated by phosphorylation on Ser-9 (not shown here because this structure start at residue 35). Furthermore the phosphorylation on Tyr-216 is not mandatory for the activity,<ref>"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</ref>.

Arg-141 is one of the key residues for <scene name='Sandbox_Reserved_708/Adp_recognition_by_arg141/1'>specific ATP/ADP recognition</scene> by TPK I/GSK3. In this structure no residues are phosphorylated but the orientation of the activation loop in TPK I/GSK3  is similar to that in phosphorylated CDK2 and ERK2, suggesting that TPK I/GSK3  falls into a conformation that enables it to be constitutively active* <ref>"Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3"