The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding

Sergio E. Martinez, Albert Y. Wu, Natalie A. Glavas, Xiao Bo Tang, Stewart Turley, Wim G.J. Hol, Joseph A. Beavo

Research output: Contribution to journalArticlepeer-review

233 Scopus citations

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) regulate all pathways that use cGMP or cAMP as a second messenger. Five of the 11 PDE families have regulatory segments containing GAF domains, 3 of which are known to bind cGMP. In PDE2 binding of cGMP to the GAF domain causes an activation of the catalytic activity by a mechanism that apparently is shared even in the adenylyl cyclase of Anabaena, an organism separated from mouse by 2 billion years of evolution. The 2.9-Å crystal structure of the mouse PDE2A regulatory segment reported in this paper reveals that the GAF A domain functions as a dimerization locus. The GAF B domain shows a deeply buried cGMP displaying a new cGMP-binding motif and is the first atomic structure of a physiological cGMP receptor with bound cGMP. Moreover, this cGMP site is located well away from the region predicted by previous mutagenesis and structural genomic approaches.

Original languageEnglish
Pages (from-to)13260-13265
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number20
DOIs
StatePublished - 1 Oct 2002
Externally publishedYes

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