Molecular Basis for Regulatory Subunit Diversity in cAMP-Dependent Protein Kinase

  • Diller T
  • Madhusudan
  • Xuong N
  • et al.
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Abstract

Background: Cyclic AMP binding domains possess common structural features yet are diversely coupled to different signaling modules. Each cAMP binding domain receives and transmits a cAMP signal; however, the signaling networks differ even within the same family of regulatory proteins as evidenced by the long-standing biochemical and physiological differences between type I and type II regulatory subunits of cAMP-dependent protein kinase. Results: We report the first type II regulatory subunit crystal structure, which we determined to 2.45 Å resolution and refined to an R factor of 0.176 with a free R factor of 0.198. This new structure of the type IIβ regulatory subunit of cAMP-dependent protein kinase demonstrates that the relative orientations of the two tandem cAMP binding domains are very different in the type IIβ as compared to the type Iα regulatory subunit. Each structural unit for binding cAMP contains the highly conserved phosphate binding cassette that can be considered the “signature” motif of cAMP binding domains. This motif is coupled to nonconserved regions that link the cAMP signal to diverse structural and functional modules. Conclusions: Both the diversity and similarity of cAMP binding sites are demonstrated by this new type II regulatory subunit structure. The structure represents an intramolecular paradigm for the cooperative triad that links two cAMP binding sites through a domain interface to the catalytic subunit of cAMP-dependent protein kinase. The domain interface surface is created by the binding of only one cAMP molecule and is enabled by amino acid sequence variability within the peptide chain that tethers the two domains together.

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Diller, T. C., Madhusudan, Xuong, N.-H., & Taylor, S. S. (2001). Molecular Basis for Regulatory Subunit Diversity in cAMP-Dependent Protein Kinase. Structure, 9(1), 73–82. https://doi.org/10.1016/s0969-2126(00)00556-6

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