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PNAS 99 (20): 13260-13265

Copyright © 2002 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / PHARMACOLOGY

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{dagger}, Wim G. J. Hol*,{dagger}, and Joseph A. Beavo*,{ddagger}

Departments of *Pharmacology, and {dagger}Biochemistry and Biological Structure, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195

Received for publication June 22, 2002.

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.

{ddagger} To whom reprint requests should be addressed. E-mail: beavo{at}u.washington.edu.

Edited by Lutz Birnbaumer, National Institutes of Health, Research Triangle Park, NC, and approved July 22, 2002

This paper was submitted directly (Track II) to the PNAS office.

Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID code 1MC0).

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