Work from the groups of Rachel Klevit, Professor of Biochemistry and Joseph Beavo, Professor of Pharmacology, was selected as the Journal Cover and Paper of the Week for September 19, 2008 issues of the Journal of Biological Chemistry. |
The process of vision is a fine tuned and closely regulated signal transduction pathway. One of the main players in this process is photoreceptor phosphodiesterase (PDE6), which stimulates light detection by regulating the intracellular levels of cyclic GMP in rod and cone photoreceptors. The interaction between cGMP and the regulatory domain of PDE6 affects how quickly the eye can see. When it is activated by light, the regulatory region of PDE6, referred to as GAF A, activates PDE6. PDE6 in turn degrades cGMP, ultimately allowing the brain to receive information from the retina.
To investigate the structural basis of the regulation mechanism of PDE6, Clemens Heikaus, a graduate student in the Klevit group teamed up with Dr. Sergio Martinez, a crystallographer from the Beavo group. Together, they solved the crystal structure of the cGMP-bound GAF A domain, described its functional significance and investigated the cGMP-dependent conformational change by NMR. These results provide valuable information for understanding the allosteric regulation of both the visual signaling pathway and other GAF-containing proteins. The structure is the first view of any domain from PDE6 at atomic resolution.
For the cover image, author Clemens Heikaus persuaded Brad Clifton in the Department of Ophthalmology to photograph Heikaus's own iris. Heikaus then superimposed the crystal structure onto the center of his pupil to create the image.
For more information, see article and author profiles:
Sergio E. Martinez*, Clemens C. Heikaus*, Rachel E. Klevit, Joseph A. Beavo (2008) “The Structure of the GAF A Domain from Phosphodiesterase 6C Reveals Determinants of cGMP-Binding, a Conserved Binding Surface, and a Large cGMP-Dependent Conformational Change” J. Biol. Chem. 283, 25913-25919. *These authors contributed equally.
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