Pseudoscaffolds and anchoring proteins: the difference is in the details

Abstract

Pseudokinases and pseudophosphatases possess the ability to bind substrates without catalyzing their modification, thereby providing a mechanism to recruit potential phosphotargets away from active enzymes. Since many of these pseudoenzymes possess other characteristics such as localization signals, separate catalytic sites, and protein-protein interaction domains, they have the capacity to influence signaling dynamics in local environments. In a similar manner, the targeting of signaling enzymes to subcellular locations by A-kinase-anchoring proteins (AKAPs) allows for precise and local control of second messenger signaling events. Here, we will discuss how pseudoenzymes form 'pseudoscaffolds' and compare and contrast this compartment-specific regulatory role with the signal organization properties of AKAPs. The mitochondria will be the focus of this review, as they are dynamic organelles that influence a broad range of cellular processes such as metabolism, ATP synthesis, and apoptosis.

Keywords: A-kinase-anchoring protein; mitochondria; pseudoscaffold.

Figure 1. Comparison of pseudoenzyme scaffolds and AKAPs

(A) Pseudoenzymes can act as an inhibitory anchor by binding and recruiting substrate protein away from active kinases and into a pseudoenzyme scaffold or ‘pseudoscaffold,’ thereby preventing substrate phosphorylation. This pseudoscaffold can possess additional features or functionalities such as (1) organelle-targeting motifs (i.e. mitochondrial, such as ADCK3), (2) separate catalytic sites (i.e. GTPase, such as MTMR5/13), or (3) other protein-protein interaction domains (i.e. heterodimerization, such as HER3; or other regulatory enzymes and their substrates, such as Trib2). Similarly, (B) AKAPs are a family of non-catalytic scaffolding proteins that, by definition, anchor the kinase PKA. In addition to PKA anchoring, AKAPs have also been shown to interact with a variety of other signaling molecules such as PDEs, phosphatases, and even other kinases. Many AKAPs also contain organelle-targeting motifs (i.e. mitochondrial, such as D-AKAP1). Through these additional features, both of these non-catalytic protein scaffolds can exhibit exquisite control of subcellular microdomains.