Initiation of the 3′:5′-AMP-Induced Protein Kinase A Iα Regulatory Subunit Conformational Transition. Part I. A202 and A326 Are Critical Residues

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O. N. Rogacheva^1*, B. F. Shchegolev², V. E. Stefanov¹, G. A. Zakharov², and E. V. Savvateeva-Popova²

¹St. Petersburg State University, Universitetskaya nab. 7/9, 199034 St. Petersburg, Russia; E-mail: AcerLaetum@yandex.ru

²Pavlov Institute of Physiology, Russian Academy of Sciences, nab. Makarova 6, 199034 St. Petersburg, Russia

^* To whom correspondence should be addressed.

Received January 12, 2012

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Protein–ligand docking and molecular dynamics studies have shown that the key event initiated by 3′:5′-AMP binding to the A- and B-domains of protein kinase A Iα regulatory subunit is formation of a hydrogen bond between 3′:5′-AMP and A202(A326) (the residue in parentheses being from the B-domain). The A202(A326) amide group movement associated with the bond formation leads to reorganization of the phosphate binding cassette (PBC) (the short 3₁₀-helix becomes the long α-helix). This process results in L203(L327) displacement and finally causes hinge (B-helix) rotation. The L203(L327) displacement and packing into the hydrophobic pocket formed by the PBC and β2β3-loop also depends on the β2β3-loop conformation. The correct conformation is maintained by R, I, E, but not K at position 209(333) of the A- and B-domains. So, the R209K and R333K mutants have problems with reaching B-conformation. The apo-form of the 3′:5′-AMP-binding domain also undergoes transition from H- to B-conformation. In this case, the movement of A202(A326) amide group seems to be a result of reorganization of the PBC into a more stable α-helix.

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KEY WORDS: A- and B-domains of PKA Iα R-subunit, 3′:5′-AMP, A202(A326), molecular dynamics, β2β3-loop, phosphate binding cassette

DOI: 10.1134/S0006297912050057

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