Non-Canonical Allostery in Cyclic Nucleotide Dependent Kinases

The cAMP-and cGMP-dependent protein kinases (PKA and PKG) are canonically activated by the cor-responding cyclic nucleotides. However, both systems are also sensitive to a wide range of non-canonical allosteric effectors, such as reactive oxygen species, which induce the formation of regulatory inter-and intra-molecular disulfide bridges, and disease-related mutations (DRMs). Here, we present a combined analysis of representative non-canonical allosteric effectors for PKA and PKG, and we identify common molecular mechanisms underlying non-canonical allostery in these kinases, from shifts in dynamical reg-ulatory equilibria to modulation of inter-protomer interactions. In addition, mutations may also drive oligomerization beyond dimerization, and possibly phase transitions, causing loss of kinase inhibitory function and amplifying the allosteric effects of DRMs. Hence non-canonical allosteric stimuli often result in constitutive kinase activation underlying either physiological control of downstream signaling pathways or pathological outcomes, from aortic aneurisms to cancer predisposition. Overall, PKA and PKG emerge as pan-sensors going well beyond canonical cyclic nucleotide activation, revealing their versatile roles as central signaling hubs.(c) 2022 Elsevier Ltd. All rights reserved.

Automated summary

The protein kinases PKA and PKG can be activated by not only cyclic nucleotides, but also a wide range of non-canonical allosteric effectors. The molecular mechanisms involve shifts in dynamical regulatory equilibria and modulation of inter-protomer interactions. Mutations can lead to constitutive kinase activation, resulting in physiological or pathological outcomes.