| Structural highlights
Function
GSK3A_HUMAN Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1 (PubMed:11749387, PubMed:17478001, PubMed:19366350). Requires primed phosphorylation of the majority of its substrates (PubMed:11749387, PubMed:17478001, PubMed:19366350). Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:11749387, PubMed:17478001, PubMed:19366350). Regulates glycogen metabolism in liver, but not in muscle (By similarity). May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:10868943, PubMed:17478001). In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin (PubMed:17229088). Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease (PubMed:12761548). May be involved in the regulation of replication in pancreatic beta-cells (By similarity). Is necessary for the establishment of neuronal polarity and axon outgrowth (By similarity). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions which activates KAT5/TIP60 acetyltransferase activity and promotes acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (By similarity). Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075).[UniProtKB:P18265][UniProtKB:P49841][UniProtKB:Q2NL51][1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Glycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for diverse clinical indications. However, one hurdle in the development of small molecule GSK3 inhibitors has been safety concerns related to pan-inhibition of both GSK3 paralogs, leading to activation of the Wnt/beta-catenin pathway and potential for aberrant cell proliferation. Development of GSK3alpha or GSK3beta paralog-selective inhibitors that could offer an improved safety profile has been reported but further advancement has been hampered by the lack of structural information for GSK3alpha. Here we report for the first time the crystal structure for GSK3alpha, both in apo form and bound to a paralog-selective inhibitor. Taking advantage of this new structural information, we describe the design and in vitro testing of novel compounds with up to approximately 37-fold selectivity for GSK3alpha over GSK3beta with favorable drug-like properties. Furthermore, using chemoproteomics, we confirm that acute inhibition of GSK3alpha can lower tau phosphorylation at disease-relevant sites in vivo, with a high degree of selectivity over GSK3beta and other kinases. Altogether, our studies advance prior efforts to develop GSK3 inhibitors by describing GSK3alpha structure and novel GSK3alpha inhibitors with improved selectivity, potency, and activity in disease-relevant systems.
Elucidation of the GSK3alpha Structure Informs the Design of Novel, Paralog-Selective Inhibitors.,Amaral B, Capacci A, Anderson T, Tezer C, Bajrami B, Lulla M, Lucas B, Chodaparambil JV, Marcotte D, Kumar PR, Murugan P, Spilker K, Cullivan M, Wang T, Peterson AC, Enyedy I, Ma B, Chen T, Yousaf Z, Calhoun M, Golonzhka O, Dillon GM, Koirala S ACS Chem Neurosci. 2023 Mar 15;14(6):1080-1094. doi: , 10.1021/acschemneuro.2c00476. Epub 2023 Feb 22. PMID:36812145[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nikoulina SE, Ciaraldi TP, Mudaliar S, Mohideen P, Carter L, Henry RR. Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes. 2000 Feb;49(2):263-71. PMID:10868943 doi:10.2337/diabetes.49.2.263
- ↑ Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature. 2003 May 22;423(6938):435-9. PMID:12761548 doi:10.1038/nature01640
- ↑ Asuni AA, Hooper C, Reynolds CH, Lovestone S, Anderton BH, Killick R. GSK3alpha exhibits beta-catenin and tau directed kinase activities that are modulated by Wnt. Eur J Neurosci. 2006 Dec;24(12):3387-92. PMID:17229088 doi:10.1111/j.1460-9568.2006.05243.x
- ↑ Koo J, Wu X, Mao Z, Khuri FR, Sun SY. Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation. J Biol Chem. 2015 May 29;290(22):14120-9. PMID:25897075 doi:10.1074/jbc.M114.633057
- ↑ Cheng X, Ma X, Zhu Q, Song D, Ding X, Li L, Jiang X, Wang X, Tian R, Su H, Shen Z, Chen S, Liu T, Gong W, Liu W, Sun Q. Pacer Is a Mediator of mTORC1 and GSK3-TIP60 Signaling in Regulation of Autophagosome Maturation and Lipid Metabolism. Mol Cell. 2019 Feb 21;73(4):788-802.e7. PMID:30704899 doi:10.1016/j.molcel.2018.12.017
- ↑ Ali A, Hoeflich KP, Woodgett JR. Glycogen synthase kinase-3: properties, functions, and regulation. Chem Rev. 2001 Aug;101(8):2527-40. PMID:11749387 doi:10.1021/cr000110o
- ↑ Lee J, Kim MS. The role of GSK3 in glucose homeostasis and the development of insulin resistance. Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S49-57. PMID:17478001 doi:10.1016/j.diabres.2007.01.033
- ↑ Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A. Glycogen synthase kinase 3: more than a namesake. Br J Pharmacol. 2009 Mar;156(6):885-98. PMID:19366350 doi:10.1111/j.1476-5381.2008.00085.x
- ↑ Amaral B, Capacci A, Anderson T, Tezer C, Bajrami B, Lulla M, Lucas B, Chodaparambil JV, Marcotte D, Kumar PR, Murugan P, Spilker K, Cullivan M, Wang T, Peterson AC, Enyedy I, Ma B, Chen T, Yousaf Z, Calhoun M, Golonzhka O, Dillon GM, Koirala S. Elucidation of the GSK3α Structure Informs the Design of Novel, Paralog-Selective Inhibitors. ACS Chem Neurosci. 2023 Mar 15;14(6):1080-1094. PMID:36812145 doi:10.1021/acschemneuro.2c00476
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