4fkd

Identification of the Activator Binding Residues in the Second Cysteine-Rich Regulatory Domain of Protein Kinase C ThetaIdentification of the Activator Binding Residues in the Second Cysteine-Rich Regulatory Domain of Protein Kinase C Theta

Structural highlights 4fkd is a 1 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: Gene: Prkcq, Pkcq (LK3 transgenic mice) Activity: Protein kinase C, with EC number 2.7.11.13 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [KPCT_MOUSE] Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates to the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1. Publication Abstract from PubMed PKCtheta is predominantly expressed in T-cells and critically involved in immunity. Design of PKCtheta selective molecules to manage autoimmune disorders by targeting its activator binding C1 domain requires the knowledge of its structure and the activator binding residues. The C1 domain consists of twin C1 domains, C1A and C1B, of which C1B plays the critical role in the membrane translocation and activation of PKCq. Here, we determined the crystal structure of the PKCthetaC1B to 1.63A resolution, which showed that the Trp-253 at the rim of the activator binding pocket was oriented towards the membrane whereas in PKCdC1B, the homologous tryptophan was oriented away from the membrane. This particular orientation of Trp-253 abolishes the possible p-stacking interactions between Trp-253 and His-270 and the cation-p interactions between Trp-253 and Arg-272, which are present between the homologous residues in PKCdC1B. To further probe the structural constraints on activator binding, five residues lining the activator binding site were mutated (Y239A, T243A, W253G, L255G and Q258G) and the binding affinities of the PKCthetaC1B mutants were measured. These mutants showed reduced binding affinities for phorbol ester (PDBu) and diacylglycerol (DOG). All the five full length PKCtheta mutants exhibited reduced phorbol ester-induced membrane translocation compared to the wild type. These results provide insights into the PKCq activator binding domain, which will aid in future design of PKCtheta selective molecules. Identification of the Activator Binding Residues in the Second Cysteine-Rich Regulatory Domain of Protein Kinase C Theta.,Rahman GM, Shanker S, Lewin NE, Kedei N, Hill CS, Prasad BV, Blumberg P, Das J Biochem J. 2013 Jan 4. PMID:23289588 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Protein kinase C

spinqualitylabelsall models 4fkd, resolution 1.63Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image