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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 and Joseph A. Beavo
Proceedings of the National Academy of Sciences of the United States of America
Vol. 99, No. 20 (Oct. 1, 2002), pp. 13260-13265
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3073384
Page Count: 6
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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.
Proceedings of the National Academy of Sciences of the United States of America © 2002 National Academy of Sciences