Download MendeleyStructural Basis of Cyclic Nucleotide Selectivity in cGMP-dependent Protein Kinase II.
Campbell, J.C., Kim, J.J., Li, K.Y., Huang, G.Y., Reger, A.S., Matsuda, S., Sankaran, B., Link, T.M., Yuasa, K., Ladbury, J.E., Casteel, D.E., Kim, C.(2016) J Biol Chem 291: 5623-5633
- PubMed: 26769964
- DOI: https://doi.org/10.1074/jbc.M115.691303
- Primary Citation of Related Structures:
5BV6, 5C6C, 5C8W - PubMed Abstract:
Membrane-bound cGMP-dependent protein kinase (PKG) II is a key regulator of bone growth, renin secretion, and memory formation. Despite its crucial physiological roles, little is known about its cyclic nucleotide selectivity mechanism due to a lack of structural information. Here, we find that the C-terminal cyclic nucleotide binding (CNB-B) domain of PKG II binds cGMP with higher affinity and selectivity when compared with its N-terminal CNB (CNB-A) domain. To understand the structural basis of cGMP selectivity, we solved co-crystal structures of the CNB domains with cyclic nucleotides. Our structures combined with mutagenesis demonstrate that the guanine-specific contacts at Asp-412 and Arg-415 of the ¦ÁC-helix of CNB-B are crucial for cGMP selectivity and activation of PKG II. Structural comparison with the cGMP selective CNB domains of human PKG I and Plasmodium falciparum PKG (PfPKG) shows different contacts with the guanine moiety, revealing a unique cGMP selectivity mechanism for PKG II.
Organizational Affiliation:
From the Structural and Computational Biology and Molecular Biophysics Program.
