Insight into intra- and inter-molecular interactions of PKC: design of specific modulators of kinase function - PubMed (original) (raw)
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Insight into intra- and inter-molecular interactions of PKC: design of specific modulators of kinase function
Viktoria Kheifets et al. Pharmacol Res. 2007 Jun.
Abstract
Protein kinase C (PKC) is a family of kinases that are critical in many cellular events. These enzymes are activated by lipid-derived second messengers, are dependent on binding to negatively charged phospholipids and some members also require calcium to attain full activation. The interaction with lipids and calcium activators is mediated by binding to the regulatory domains C1 and C2. In addition, many protein-protein interactions between PKC and other proteins have been described. These include interactions with adaptor proteins, substrates and cytoskeletal elements. Regulation of the interactions between PKC, small molecules and other proteins is essential for signal transduction to occur. Finally, a number of auto-inhibitory intra-molecular protein-protein interactions have also been identified in PKC. This chapter focuses on mapping the sites for many of these inter- and intra-molecular interactions and how this information may be used to generate selective inhibitors and activators of PKC signaling.
Figures
Figure 1. PKC family of isozymes
The PKC family of isozymes consists of three classes: the classical (α, βI, βII, γ), novel (ε, δ, θ), and atypical (η,λ/ι) The regulatory domain consists of the C1 and C2 domains, and variable regions (V) 1-3. The V1 region contains the Ψsubstrate sequence (red) that binds the substrate binding site of the catalytic domain; the Ψsubstrate sequence is the most well-known example of inhibitory intramolecular interaction. The classical and novel families contain a duplicate of the C1 domain (light blue) that binds DAG and its analogs, whereas the atypical family contains only one C1 copy. The classical and novel families contain a C2 domain (dark blue), which binds to phosphatidylserine; the classical C2 binds PS in a calcium-dependent manner. The catalytic domain consists of the ATP binding domain C3 (light green) and substrate binding/catalytic domain C4 (dark green). The C-terminus of the protein contains the V5 domain, which contains phosphorylation sites that regulate PKC activity.
Figure 2. A schematic showing how some inter- and intra- molecular interactions are disrupted and others established when PKC is activated
PKC contains several intra-molecular interactions that keep the enzyme in the inactive state. For simplicity, we focus on one such interaction between the RACK binding site and a site in PKC that is homologous to the RACK sequence and is therefore termed pseudoRACK. These intra-molecular interactions can be disrupted spontaneously to create an open transition state. However, most of the time, the inter-molecular interactions are maintained. When there is a rise in diacylglycerol (DAG) (and calcium for the calcium-sensitive PKCs) or when cells are treated with the tumor promoter phorbol ester (PMA), the open state is stabilized by binding of the enzyme to membranes and the corresponding RACK, resulting in its anchoring nearby a particular substrate and away from others. The numerous intra- and inter-molecular interactions can be disrupted to yield selective regulators of PKC functions.
Figure 3. PKC inter- and intra- molecular interaction sites mapped on individual PKC domains
A. Interactions are mapped on the δC1b domain (adapted from 1PTQ (93)) crystallized with PMA (stick figure) and zinc (green). Regions responsible for neurite outgrowth are indicated in green (42), nuclear localization sequence in purple (43), and golgi localization signal (94) in blue. Intersection of green and purple region is indicated in yellow. Lower panel shows the schematic of the domain with color-coded interaction regions. B. Interactions are mapped on the αC2 domain (adapted from 1DSY (95)) crystallized with phosphatidylserine (stick figure) and calcium (green). Regions responsible for RACK binding (red (60)), PIP2 binding (dark blue (50)), lamin binding (green (92)) and the ΨRACK site (purple (62)) are indicated. Intersection of green and red region is indicated in yellow. Lower panel shows the schematic of the domain with color-coded interaction regions. C. Interactions are mapped on the ιPKC catalytic domain (adapted from 1ZRZ (79)) crystallized with bis(indolyl)maleimide inhibitor (BIM1). Regions responsible for RACK binding (red (82)), nuclear localization sequence (purple (87)), phosphatidylglycerol binding (green (84)), PDZ interaction domain (black (85)), and V5/catalytic core interactions (light and dark blue (79)) are indicated. The front and back of the structure is shown for ease of visualization. Intersection of green and red region is indicated in yellow. Lower panel shows the schematic of the domain with color-coded interaction regions.
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