7LZ4

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

Summary for 7LZ4

• Entry DOI: 10.2210/pdb7lz4/pdb
• Descriptor: cAMP-dependent protein kinase type I-alpha regulatory subunit, N-terminally processed, ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE (2 entities in total)
• Functional Keywords: carney complex, cyclic nucleotide binding domain, cyclic amp (camp), protein kinase a (pka), transferase
• Biological source: Bos taurus (Bovine)
• Total number of polymer chains: 8
• Total formula weight: 248022.89

Authors

Del Rio, J.,Wu, J.,Taylor, S.S. (deposition date: 2021-03-08, release date: 2021-05-26, Last modification date: 2023-10-18)

Primary citation

Jafari, N.,Del Rio, J.,Akimoto, M.,Byun, J.A.,Boulton, S.,Moleschi, K.,Alsayyed, Y.,Swanson, P.,Huang, J.,Martinez Pomier, K.,Lee, C.,Wu, J.,Taylor, S.S.,Melacini, G.
Noncanonical protein kinase A activation by oligomerization of regulatory subunits as revealed by inherited Carney complex mutations.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Familial mutations of the protein kinase A (PKA) R1α 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 R1α 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 R1α, 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 R1α inhibitory function.

PubMed: 34006641
DOI: 10.1073/pnas.2024716118

Experimental method

X-RAY DIFFRACTION (4.155 Å)