Sandbox Reserved 708

DescritpionDescritpion

The Glycogen Synthase Kinase 3 beta- GSK3 beta, 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. GSK-3 phosphorylates a large number of substrates and is himself regulated by phosphorylation. GSK-3 is implicated in several diseases like Alzheimer’s disease, diabetes, mood disorders and cancer,. In the Alzheimer’s disease, it is thought to be tied to the process of the hyperphosphorylation of tau proteins 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. There are two isoforms of GSK-3: GSK3α et GSK3β . 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.

GSK-3β can phosphorylate tau on Ser199, Thr231, Ser396, Ser400, Ser404, and Ser413in vivo and in vitro,

ActivityActivity

spinqualitylabelsall models PDB ID 1j1c Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
1j1c, resolution 2.10Å ()
Ligands:	,
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Related:	1j1b
Structural annotation: Resources: CATH : 1J1Ca02, 1J1Ca01, 1J1Cb02, 1J1Cb01 InterPro : Ipr011009, Ipr002290, Ipr008271, Ipr000719 Pfam : PF00069 SCOP : d1j1ca_, d1j1cb_ UniProt : P49841
Functional annotation: Cellular component: cytoplasm nucleus beta-catenin destruction complex Biological process: ER overload response positive regulation of protein export from nucleus peptidyl-serine phosphorylation glycogen metabolic process protein amino acid phosphorylation Wnt receptor signaling pathway through beta-catenin intracellular signaling cascade negative regulation of apoptosis Wnt receptor signaling pathway Molecular function: nucleotide binding kinase activity transferase activity ATP binding protein binding protein serine/threonine kinase activity NF-kappaB binding glycogen synthase kinase 3 activity protein kinase activity p53 binding
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, RCSB, PDBsum
Coordinates:	save as pdb, mmCIF, xml

As the EC code says it, The Tau protein is a transferase but belongs to two different classes,:

• 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

,This is the Ramachandran plot of 1j1c, here there is a link to understand this diagram. As this diagram shows it the binary complex have β-sheets and α-helixes.

This complex is composed by two subunits A (green) and B (blue) linked by 12 hydrogen bonds in order to stabilize the molecule. But in this case only four are shown (with red dashed lines) with there 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.

This structure also possesses as well as (Adenosine DiPhosphate).

These are the engaged in the catalytic site of the protein, they are polar and localised in 3' end: Asp-181, Lys-183, Gln-185, Asn-186 and Ser-219.

This enzyme is activated by phosphorylation at and inactivated by phosphorylation at Ser-9 (not shown here because this structure start at residue 35). Furthermore the phosphorylation at Tyr-216 is not mandatory for the activity,.

Arg-141 is one of the key residues for 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* .

This structure possesse 2 domains according to the CATH structural classification:

• [1]
• [2]

External RessourcesExternal Ressources

Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 abstract M. Aoki, T. Yokota, I. Sugiura, C. Sasaki, T. Hasegawa, C. Okumura, K. Ishiguro, T. Kohno, S. Sugio and T. Matsuzaki