Conformation changes, N-terminal involvement and cGMP signal relay in phosphodiesterase-5 GAF domain
Abstract
The activity of phosphodiesterase-5 (PDE5) is specific for cGMP and is regulated by cGMP binding to GAF-A in its regulatory domain. To better understand the regulatory mechanism, x-ray crystallographic and biochemical studies were performed on constructs of human PDE5A1 containing the N-terminal phosphorylation segment, GAF-A, and GAF-B. Superposition of this unliganded GAF-A with the previously reported NMR structure of cGMP-bound PDE5 revealed dramatic conformational differences and suggested that helix H4 and strand B3 probably serve as two lids to gate the cGMP-binding pocket in GAF-A. The structure also identified an interfacial region among GAF-A, GAF-B, and the N-terminal loop, which may serve as a relay of the cGMP signal from GAF-A to GAF-B. N-terminal loop 98-147 was physically associated with GAF-B domains of the dimer. Biochemical analyses showed an inhibitory effect of this loop on cGMP binding and its involvement in the cGMP-induced conformation changes.
- Authors:
- Publication Date:
- Research Org.:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE SC OFFICE OF SCIENCE (SC)
- OSTI Identifier:
- 1040560
- Report Number(s):
- BNL-94517-2011-JA
Journal ID: ISSN 0021-9258; JBCHA3; R&D Project: BO-070; KP1605010; TRN: US201210%%736
- DOE Contract Number:
- DE-AC02-98CH10886
- Resource Type:
- Journal Article
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 285; Journal Issue: 49; Journal ID: ISSN 0021-9258
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CRYSTAL STRUCTURE; NUCLEOTIDES; PHOSPHODIESTERASES; PHOSPHORYLATION
Citation Formats
Wang, H, Robinson, H, and Ke, H. Conformation changes, N-terminal involvement and cGMP signal relay in phosphodiesterase-5 GAF domain. United States: N. p., 2010.
Web. doi:10.1074/jbc.M110.141614.
Wang, H, Robinson, H, & Ke, H. Conformation changes, N-terminal involvement and cGMP signal relay in phosphodiesterase-5 GAF domain. United States. https://doi.org/10.1074/jbc.M110.141614
Wang, H, Robinson, H, and Ke, H. 2010.
"Conformation changes, N-terminal involvement and cGMP signal relay in phosphodiesterase-5 GAF domain". United States. https://doi.org/10.1074/jbc.M110.141614.
@article{osti_1040560,
title = {Conformation changes, N-terminal involvement and cGMP signal relay in phosphodiesterase-5 GAF domain},
author = {Wang, H and Robinson, H and Ke, H},
abstractNote = {The activity of phosphodiesterase-5 (PDE5) is specific for cGMP and is regulated by cGMP binding to GAF-A in its regulatory domain. To better understand the regulatory mechanism, x-ray crystallographic and biochemical studies were performed on constructs of human PDE5A1 containing the N-terminal phosphorylation segment, GAF-A, and GAF-B. Superposition of this unliganded GAF-A with the previously reported NMR structure of cGMP-bound PDE5 revealed dramatic conformational differences and suggested that helix H4 and strand B3 probably serve as two lids to gate the cGMP-binding pocket in GAF-A. The structure also identified an interfacial region among GAF-A, GAF-B, and the N-terminal loop, which may serve as a relay of the cGMP signal from GAF-A to GAF-B. N-terminal loop 98-147 was physically associated with GAF-B domains of the dimer. Biochemical analyses showed an inhibitory effect of this loop on cGMP binding and its involvement in the cGMP-induced conformation changes.},
doi = {10.1074/jbc.M110.141614},
url = {https://www.osti.gov/biblio/1040560},
journal = {Journal of Biological Chemistry},
issn = {0021-9258},
number = 49,
volume = 285,
place = {United States},
year = {Fri Dec 03 00:00:00 EST 2010},
month = {Fri Dec 03 00:00:00 EST 2010}
}