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

Abstract

Membrane-bound cGMP-dependent protein kinase (PKG) II is an important 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 PKGII 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.

Authors:
 [1];  [2];  [3];  [1];  [1];  [4];  [5];  [6];  [4];  [7];  [8];  [1]
+ Show Author Affiliations
  1. Baylor College of Medicine, Houston, TX (United States)
  2. Baylor College of Medicine, Houston, TX (United States); Univ. of Kassel, Hesse (Germany)
  3. Rice Univ., Houston, TX (United States)
  4. Univ. of Tokushima Graduate School (Japan)
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  6. Univ. of Texas M.D. Anderson Cancer Center, Houston, TX (United States)
  7. Baylor College of Medicine, Houston, TX (United States); Univ. of Texas M.D. Anderson Cancer Center, Houston, TX (United States)
  8. Univ. of California, San Diego, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1379155
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 291; Journal Issue: 11; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Campbell, James C., Kim, Jeong Joo, Li, Kevin Y., Huang, Gilbert Y., Reger, Albert S., Matsuda, Shinya, Sankaran, Banumathi, Link, Todd M., Yuasa, Keizo, Ladbury, John E., Casteel, Darren E., and Kim, Choel. Structural Basis of Cyclic Nucleotide Selectivity in cGMP-dependent Protein Kinase II. United States: N. p., 2016. Web. doi:10.1074/jbc.M115.691303.
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Campbell, James C., Kim, Jeong Joo, Li, Kevin Y., Huang, Gilbert Y., Reger, Albert S., Matsuda, Shinya, Sankaran, Banumathi, Link, Todd M., Yuasa, Keizo, Ladbury, John E., Casteel, Darren E., & Kim, Choel. Structural Basis of Cyclic Nucleotide Selectivity in cGMP-dependent Protein Kinase II. United States. https://doi.org/10.1074/jbc.M115.691303
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Campbell, James C., Kim, Jeong Joo, Li, Kevin Y., Huang, Gilbert Y., Reger, Albert S., Matsuda, Shinya, Sankaran, Banumathi, Link, Todd M., Yuasa, Keizo, Ladbury, John E., Casteel, Darren E., and Kim, Choel. Thu . "Structural Basis of Cyclic Nucleotide Selectivity in cGMP-dependent Protein Kinase II". United States. https://doi.org/10.1074/jbc.M115.691303. https://www.osti.gov/servlets/purl/1379155.
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@article{osti_1379155,
title = {Structural Basis of Cyclic Nucleotide Selectivity in cGMP-dependent Protein Kinase II},
author = {Campbell, James C. and Kim, Jeong Joo and Li, Kevin Y. and Huang, Gilbert Y. and Reger, Albert S. and Matsuda, Shinya and Sankaran, Banumathi and Link, Todd M. and Yuasa, Keizo and Ladbury, John E. and Casteel, Darren E. and Kim, Choel},
abstractNote = {Membrane-bound cGMP-dependent protein kinase (PKG) II is an important 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 PKGII 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.},
doi = {10.1074/jbc.M115.691303},
journal = {Journal of Biological Chemistry},
number = 11,
volume = 291,
place = {United States},
year = {Thu Jan 14 00:00:00 EST 2016},
month = {Thu Jan 14 00:00:00 EST 2016}
}
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https://doi.org/10.1074/jbc.M115.691303
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