Structural Basis of Cyclic Nucleotide Selectivity in cGMP-dependent Protein Kinase II.

The Journal of Biological Chemistry
James C CampbellChoel Kim

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 αC-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.

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Citations

Jun 27, 2019·Proceedings of the National Academy of Sciences of the United States of America·Majida El BakkouriRaymond Hui
Dec 4, 2020·Protein Science : a Publication of the Protein Society·Choel Kim, Rajesh Sharma
Oct 28, 2020·Journal of Medical Genetics·Francisca Díaz-GonzálezKaren E Heath
Mar 30, 2021·Frontiers in Molecular Biosciences·Florencia KleinSergio Pantano
Jun 12, 2021·The Journal of Physical Chemistry. B·Jinfeng HuangGiuseppe Melacini
Aug 10, 2017·ACS Chemical Biology·James C CampbellChoel Kim

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