Hypothesis: Unifying model of domain architecture for conventional and novel protein kinase C isozymes

Abstract

Protein kinase C (PKC) family members are multi‐domain proteins whose function is exquisitely tuned by interdomain interactions that control the spatiotemporal dynamics of their signaling. Despite extensive mechanistic studies on this family of enzymes, no structure of a full‐length enzyme that includes all domains has been solved. Here, we take into account the biochemical mechanisms that control autoinhibition, the properties of each individual domain, and previous structural studies to propose a unifying model for the general architecture of PKC family members. This model shows how the C2 domains of conventional and novel PKC isozymes, which have different topologies and different positions in the primary structure, can occupy the same position in the tertiary structure of the kinase. This common architecture of conventional and novel PKC isozymes provides a framework for understanding how disease‐associated mutations impair PKC function.

Protein Kinase Cγ Mutations Drive Spinocerebellar Ataxia Type 14 by Impairing Autoinhibition

“…To illuminate how SCA14 mutants might interfere with autoinhibition, we mapped mutations in the C1B and kinase domains on the PKCγ model, generated using the previously published model of PKCβII as a prototype (16). Indeed, many of these mutations exist in domains and at interfaces expected to interfere with autoinhibition of the kinase.…”

“…Lastly, we used a homology model for the architecture of conventional PKC isozymes (16) to predict where the 54 known SCA14-associated mutations (Fig. 1A) would occur within the 3dimensional structure of PKCγ (Fig.…”

“…Additionally, multiple interactions of the kinase domain with modules in the regulatory moiety secure the pseudosubstrate in place to prevent aberrant basal signaling. These modules are the DG-sensing C1A and C1B domains and Ca 2+ -sensing C2 domain, which pack against the kinase domain to maintain it in an autoinhibited conformation until the relevant second messengers are generated (16). Release of the pseudosubstrate occurs upon generation of the appropriate second messengers.…”

Two Sides of the Same Coin: Protein Kinase C γ in Cancer and Neurodegeneration

“…A partial crystal structure of PKCβII was previously solved, however multiple domains remained unresolved due to inadequate electron density (Leonard et al, 2011). Refining this structure, Leonard and others concluded that conventional and novel PKC isozymes share a common 3D architecture, (Jones et al, 2020;Pilo et al, 2022), showing kinase domain as cyan surface, and the C1 domains and C2 domains in ribbon representation. SCA14 mutations, represented as red spheres, are concentrated in C1B domain or interfaces with the kinase domain.…”

“…Arrows indicate linker direction. (C) Hypothetical model of PKCγ structure based on the previously published model for general architecture of PKC isozymes ( Jones et al, 2020 ; Pilo et al, 2022 ), showing kinase domain as cyan surface, and the C1 domains and C2 domains in ribbon representation. SCA14 mutations, represented as red spheres, are concentrated in C1B domain or interfaces with the kinase domain.…”