1a25
C2 DOMAIN FROM PROTEIN KINASE C (BETA)
Structural highlights
FunctionKPCB_RAT 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] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBACKGROUND: Conventional isoforms (alpha, beta and gamma) of protein kinase C (PKC) are synergistically activated by phosphatidylserine and Ca2+; both bind to C2 domains located within the PKC amino-terminal regulatory regions. C2 domains contain a bipartite or tripartite Ca2+-binding site formed by opposing loops at one end of the protein. Neither the structural basis for cooperativity between phosphatidylserine and Ca2+, nor the binding site for phosphatidylserine are known. RESULTS: The structure of the C2 domain from PKCbeta complexed with Ca2+ and o-phospho-L-serine has been determined to 2.7 A resolution using X-ray crystallography. The eight-stranded, Greek key beta-sandwich fold of PKCbeta-C2 is similar to that of the synaptotagmin I type I C2 domain. Three Ca2+ ions, one at a novel site, were located, each sharing common aspartate ligands. One of these ligands is donated by a dyad-related C2 molecule. A phosphoserine molecule binds to a lysine-rich cluster in C2. CONCLUSIONS: Shared ligation among the three Ca2+ ions suggests that they bind cooperatively to PKCbeta-C2. Cooperativity may be compromised by the accumulation of positive charge in the binding site as successive ions are bound. Model building shows that the C1 domain could provide carboxylate and carbonyl ligands for two of the three Ca2+ sites. Ca2+-mediated interactions between the two domains could contribute to enzyme activation as well as to the creation of a positively charged phosphatidylserine-binding site. Structure of the protein kinase Cbeta phospholipid-binding C2 domain complexed with Ca2+.,Sutton RB, Sprang SR Structure. 1998 Nov 15;6(11):1395-405. PMID:9817842[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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