Noncanonical protein kinase A activation by oligomerization of regulatory subunits as revealed by inherited Carney complex mutations

Significance Autosomal dominant mutations in one of the most ubiquitous isoforms of the inhibitory subunit (R1α) of protein kinase A (PKA) are linked to a generalized tumor predisposition, referred to as Carney complex (CNC). The molecular phenotype of CNC mutants is PKA overactivation. However, explaining PKA overactivation remains an unmet challenge for some of the most harmful CNC mutants, which are expressed and exhibit significantly reduced affinity for the cAMP activator but not for the PKA catalytic subunit (C). Here, we address this challenge by proposing a mechanism of PKA activation, distinct from the classical cAMP-dependent dissociation of the R 2 :C 2 complex and based on oligomerization of R1α into assemblies, which are incompetent to inhibit PKA C.

Noncanonical protein kinase A activation by oligomerization of regulatory subunits as revealed by inherited Carney complex mutations Journal Articles