9s9t
Structure of human PKCBeta Kinase domain with Ruboxistaurin, D427N mutant
Structural highlights
FunctionKPCB_HUMAN Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase involved in various cellular processes such as regulation of the B-cell receptor (BCR) signalosome, oxidative stress-induced apoptosis, androgen receptor-dependent transcription regulation, insulin signaling and endothelial cells proliferation. Plays a key role in B-cell activation by regulating BCR-induced NF-kappa-B activation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11/CARMA1 at 'Ser-559', 'Ser-644' and 'Ser-652'. Phosphorylation induces CARD11/CARMA1 association with lipid rafts and recruitment of the BCL10-MALT1 complex as well as MAP3K7/TAK1, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. Plays a direct role in the negative feedback regulation of the BCR signaling, by down-modulating BTK function via direct phosphorylation of BTK at 'Ser-180', which results in the alteration of BTK plasma membrane localization and in turn inhibition of BTK activity. Involved in apoptosis following oxidative damage: in case of oxidative conditions, specifically phosphorylates 'Ser-36' of isoform p66Shc of SHC1, leading to mitochondrial accumulation of p66Shc, where p66Shc acts as a reactive oxygen species producer. Acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag for epigenetic transcriptional activation that prevents demethylation of histone H3 'Lys-4' (H3K4me) by LSD1/KDM1A. In insulin signaling, may function downstream of IRS1 in muscle cells and mediate insulin-dependent DNA synthesis through the RAF1-MAPK/ERK signaling cascade. May participate in the regulation of glucose transport in adipocytes by negatively modulating the insulin-stimulated translocation of the glucose transporter SLC2A4/GLUT4. Under high glucose in pancreatic beta-cells, is probably involved in the inhibition of the insulin gene transcription, via regulation of MYC expression. In endothelial cells, activation of PRKCB induces increased phosphorylation of RB1, increased VEGFA-induced cell proliferation, and inhibits PI3K/AKT-dependent nitric oxide synthase (NOS3/eNOS) regulation by insulin, which causes endothelial dysfunction. Also involved in triglyceride homeostasis (By similarity).[1] [2] Publication Abstract from PubMedMutations in the T-cell receptor signalling pathway have been identified in patients with adult T-cell leukaemia/lymphoma (ATLL) and one of the most frequently observed targets of these mutations is protein kinase C beta (PKCbeta). Here, we have characterised the most frequent mutation in PKCbeta (D427N), addressing the issue of gain/loss of function, neomorphic change and assessing the impact of mutation in vivo, in cells, biochemically and structurally. It is concluded that this mutation is a gain-of-function, activating mutation that confers an altered substrate specificity on this protein kinase. In a constitutive knock-in mouse model, this activated allele induces splenomegaly associated with extramedullary haematopoiesis. Pharmacologically, the D427N mutant protein displays poor sensitivity to established PKCbeta inhibitors, necessitating the development of bespoke therapeutics for any ATLL intervention through this target. Such efforts could be guided by the availability of the D427N mutant-ruboxistaurin structure presented here. Penetrant PKCbeta mutation in ATLL displays a mixed gain-of-function.,Brown SJ, Briggs DC, Costello P, Yaguchi H, Bangham CR, Parker PJ, McDonald NQ Biochem J. 2025 Nov 4;482(21):BCJ20253384. doi: 10.1042/BCJ20253384. PMID:41091072[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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