Revisiting and Redesigning Light-Activated Cyclic-Mononucleotide Phosphodiesterases

Title data

Stabel, Robert ; Stüven, Birthe ; Hansen, Jan Niklas ; Körschen, Heinz G. ; Wachten, Dagmar ; Möglich, Andreas:
Revisiting and Redesigning Light-Activated Cyclic-Mononucleotide Phosphodiesterases.
In: Journal of Molecular Biology. Vol. 431 (2019) Issue 17 . - pp. 3029-3045.
ISSN 0022-2836
DOI: https://doi.org/10.1016/j.jmb.2019.07.011

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Abstract in another language

As diffusible second messengers, cyclic nucleoside monophosphates (cNMP) relay and amplify molecular signals in myriad cellular pathways. The triggering of downstream physiological responses often requires defined cNMP gradients in time and space, generated through the concerted action of nucleotidyl cyclases and phosphodiesterases (PDE). In an approach denoted optogenetics, sensory photoreceptors serve as genetically encoded, light-responsive actuators to enable the noninvasive, reversible and spatiotemporally precise control of manifold cellular processes, including cNMP metabolism. Although Nature provides efficient photoactivated nucleotidyl cyclases, light-responsive PDEs are scarce. Through modular recombination of a bacteriophytochrome photosensor and the effector of human phosphodiesterase 2A, we previously generated the light-activated, cNMP-specific phosphodiesterase LAPD. By pursuing parallel design strategies, we here report a suite of derivative PDEs with enhanced amplitude and reversibility of photoactivation. Opposite to LAPD, far-red light completely reverts prior activation by red light in several PDEs. These improved PDEs thus complement photoactivated nucleotidyl cyclases and extend the sensitivity of optogenetics to red and far-red light. More generally, our study informs future efforts directed at designing bacteriophytochrome photoreceptors.