Functional implications of assigned, assumed and assembled PKC structures

Abstract

The empirical derivation of PKC (protein kinase C) domain structures and those modelled by homology or imputed from protein behaviour have been extraordinarily valuable both in the elucidation of PKC pathway mechanisms and in the general lessons that extrapolate to other signalling pathways. For PKC family members, there are many domain/subdomain structures and models, covering all of the known domains, variably present in this family of protein serine/threonine kinases (C1, C2, PB1, HR1, kinase domains). In addition to these structures, there are a limited number of complexes defined, including the structure of the PKCε V3-14-3-3 complex. In the context of structure-driven insights into PKC pathways, there are several broadly applicable principles and mechanisms relevant to the operation of and intervention in signalling pathways. These principles have an impact in unexpected ways, from the regulation of membrane targeting, through strategies for pharmacological intervention, to biomarkers.

Evolving mechanisms of vascular smooth muscle contraction highlight key targets in vascular disease

“…The aPKCs do not have a C2 region but have a variant form of C1 and are therefore activated by PS but not Ca 2+ or DAG [156]. However, aPKCs do retain lipid-binding activity, and the C1 region confers DAG binding that is not duplicated, unlike the C1A–C1B tandem repeat found in cPKCs and nPKCs [164]. The aPKCs also uniquely encode the protein–protein-interacting Phox and Bem 1 (PB1) region in the N-terminal domain, which binds ZIP/p62, Par6, or MEK5 through a PB1-PB1 domain interaction that controls the localization of aPKCs [165].…”

Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders

“…PKC belongs to the AGC family of serine/threonine protein kinases that are related at their primary sequence and are named after the first identified ‘founding members’ cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) and PKC (Linch et al, 2014). PKC is the largest serine/threonine kinase family, comprising ~2% of the human kinome (Mellor and Parker, 1998).…”

“…The aPKCs do not have a C2 region but have a variant form of C1 and are therefore activated by PS but not Ca 2+ or DAG (Newton, 2001). However, aPKCs do retain lipid-binding activity, and the C1 region confers DAG binding that is not duplicated, unlike the C1A–C1B tandem repeat found in cPKCs and nPKCs (Linch et al, 2014). The aPKCs also uniquely encode the protein–protein-interacting Phox and Bem 1 (PB1) region in the N-terminus domain, which binds ZIP/p62, Par6, or MEK5 through a PB1-PB1 domain interaction that controls the localization of aPKCs (Hirano et al, 2004).…”

“…Phosphorylation of PKCɛ on Ser346 and Ser368 is required for binding to 14-3-3, and in turn locks the enzyme in an open, active and lipid-independent conformation (Saurin et al, 2008; Linch et al, 2014). On the other hand, direct interaction between PKCθ and 14-3-3 tau has been observed in T cells, and 14-3-3 overexpression inhibits PKCθ translocation and function (Meller et al., 1996).…”

“…This is likely due to reduced steady-state occupancy of the nucleotide-binding pocket, as the mutant PKCɛ dephosphorylation can be blocked by NaPP1. Also, following complete phorbol ester-induced dephosphorylation of the PKCɛ M468A mutant, phosphorylation can be re-established by treatment with NaPP1 (Cameron et al, 2009; Linch et al, 2014). …”