3sdm

Structure of oligomeric kinase/RNase Ire1 in complex with an oligonucleotide

spinqualitylabelsall models 3sdm, resolution 6.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3sdm is a 7 chain structure with sequence from Saccharomyces cerevisiae S288C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 6.6Å Ligands: SEP, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed ABSTRACT: BACKGROUND: Ire1 is a signal transduction protein in the endoplasmic reticulum (ER) membrane that serves to adjust the protein-folding capacity of the ER according to the needs of the cell. Ire1 signals in a transcriptional program, the "unfolded protein response" (UPR), via the coordinated action of its protein kinase and endoribonuclease (RNase) domains. We investigate how binding of cofactors to the kinase domain of Ire1 modulates its RNase activity. RESULTS: Our results suggest that the kinase domain of Ire1 initially binds cofactors without activation of the RNase domain. The RNase is activated upon a subsequent conformational rearrangement of Ire1 governed by the chemical properties of bound cofactors. The conformational step can be selectively inhibited by chemical perturbations of cofactors. Substitution of a single oxygen atom in the terminal beta-phosphate group of a potent cofactor ADP by sulfur results in ADPbetaS, a cofactor that binds to Ire1 as well as ADP, but does not activate the RNase. The RNase activity can be rescued by thiophilic metal ions, such as Mn2+ and Cd2+, revealing a functional metal ion-phosphate interaction, which controls the conformation and the RNase activity of Ire1 * ADP complex. Mutagenesis of the kinase domain suggests that this rearrangement involves movement of the C-helix, generally conserved among protein kinases. Using X-ray crystallography we show that oligomerization of Ire1 is sufficient for placing the alpha C-helix in the active, cofactor-bound-like conformation, even in the absence of cofactors. CONCLUSIONS: Our structural and biochemical evidence converges on a model that the co-factor-induced conformational change in Ire1 is coupled to oligomerization of the receptor, which, in turn, activates the RNase. The data reveal that cofactor-Ire1 interactions occur in two independent steps: binding of a cofactor to Ire1 and subsequent rearrangement of Ire1 resulting in its self-association. The pronounced allosteric effect of cofactors on protein-protein interactions involving Ire1's kinase domain suggests that protein kinases and pseudokinases encoded in metazoan genomes may use ATP pocket binding ligands similarly to exert signaling roles other than phosphoryl-transfer. Cofactor-mediated conformational control in the bifunctional kinase/RNase Ire1.,Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Stroud RM, Zhang C, Shokat KM, Walter P BMC Biol. 2011 Jul 6;9(1):48. PMID:21729334 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ire1

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