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In mammals, cGMP is generated by soluble and membrane-bound guanylyl cyclases and can be degraded by altogether eight out of 11 mammalian PDE families. Apart from cGMP-activated protein kinases and from cGMPgated cation channels 5 of the 11 PDE families are also subject to regulation by cNMP via their N-terminal tandem GAF ensembles. Four, PDE 2, 5, 6, and 11 appear to be regulated by cGMP; PDE10 is similarly regulated by cAMP. Thus, the cyclic nucleotides act as allosteric activators which enhance their own degradation at the catalytic site, i.e. they concomitantly serve as modulators of enzyme activity and as substrates. This creates a biochemical conundrum which cannot be disentangled kinetically. We use a cyanobacterial adenylyl cyclase, cyaB1, as a reporter enzyme to characterize intramolecular GAF domain signalling. This cyclase has an N-terminal GAF tandem which is similar to those in mammalian PDEs and regulates cyclase activity in a feed-forward manner using the product cAMP as an activator. Surprisingly, the GAF tandem domains of PDE 2, 5, 10, and 11 functionally couple to the cyclase and regulate it in a manner consistent with their function in the respective PDEs [1-3]. |
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