7lz4

Crystal structure of A211D mutant of Protein Kinase A RIa subunit, a Carney Complex mutation

spinqualitylabelsall models 7lz4, resolution 4.16Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7lz4 is a 8 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 4.155Å Ligands: CMP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KAP0_BOVIN Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Publication Abstract from PubMed Familial mutations of the protein kinase A (PKA) R1alpha regulatory subunit lead to a generalized predisposition for a wide range of tumors, from pituitary adenomas to pancreatic and liver cancers, commonly referred to as Carney complex (CNC). CNC mutations are known to cause overactivation of PKA, but the molecular mechanisms underlying such kinase overactivity are not fully understood in the context of the canonical cAMP-dependent activation of PKA. Here, we show that oligomerization-induced sequestration of R1alpha from the catalytic subunit of PKA (C) is a viable mechanism of PKA activation that can explain the CNC phenotype. Our investigations focus on comparative analyses at the level of structure, unfolding, aggregation, and kinase inhibition profiles of wild-type (wt) PKA R1alpha, the A211D and G287W CNC mutants, as well as the cognate acrodysostosis type 1 (ACRDYS1) mutations A211T and G287E. The latter exhibit a phenotype opposite to CNC with suboptimal PKA activation compared with wt. Overall, our results show that CNC mutations not only perturb the classical cAMP-dependent allosteric activation pathway of PKA, but also amplify significantly more than the cognate ACRDYS1 mutations nonclassical and previously unappreciated activation pathways, such as oligomerization-induced losses of the PKA R1alpha inhibitory function. Noncanonical protein kinase A activation by oligomerization of regulatory subunits as revealed by inherited Carney complex mutations.,Jafari N, Del Rio J, Akimoto M, Byun JA, Boulton S, Moleschi K, Alsayyed Y, Swanson P, Huang J, Martinez Pomier K, Lee C, Wu J, Taylor SS, Melacini G Proc Natl Acad Sci U S A. 2021 May 25;118(21). pii: 2024716118. doi:, 10.1073/pnas.2024716118. PMID:34006641 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also CAMP-dependent protein kinase 3D structures

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