Mammalian diacylglycerol kinases: molecular interactions and biological functions of selected isoforms

Abstract

The mammalian diacylglycerol kinases (DGK) are a group of enzymes having important roles in regulating many biological processes. Both the product and the substrate of these enzymes, i.e. diacylglycerol and phosphatidic acid, are important lipid signalling molecules. Each DGK isoform appears to have a distinct biological function as a consequence of its location in the cell and/or the proteins with which it associates. This review discusses three of the more extensively studied forms of this enzyme, DGKalpha, DGKvarepsilon, and DGKzeta. DGKalpha has an important role in immune function and its activity is modulated by several mechanisms. DGKvarepsilon has several unique features among which is its specificity for arachionoyl-containing substrates, suggesting its importance in phosphatidylinositol cycling. DGKzeta is expressed in many tissues and also has several mechanisms to regulate its functions. It is localized in several subcellular organelles, including the nucleus. The current state of our understanding of the properties and functions of these proteins is reviewed.

Figure 1. Structure of mammalian DGK isoforms

The ten members of the mammalian DGK family are grouped by sequence homology into five subtypes. Shown are protein motifs common to several DGKs. The significance of several of these motifs is discussed in the text. Additional motifs of uncertain significance are not shown.

Figure 2. Model of spatial DGK function

Evidence indicates that DGKs bind and modulate the activity of proteins regulated by either DAG or PA. In the left panel, a DGK binds and inhibits a DAG-activated protein. In the right panel, a DGK binds a protein and, by generating PA, increases its function.

Figure 3. D18-Q42 models of the native DGKε calculated by PepLook

Top: Snapshot of the 99 best structures provided by PepLook (left). View of the best model of each population (Prime’s structure in pink and model 2 in blue) (right). Bottom: Local RMS (window of 9 residues) along the sequence. The reference structure is the Prime. The red plot represents the mean values of all models of the Prime’s subpopulation, the blue one represents the mean value for the all models of the second subpopulation. The standard deviations clearly indicate that the two populations are homogenous. (Taken from [87])

Figure 4. D18-Q42 models of the P32A DGKε calculated by PepLook

Calculated conformations of P32A-DGKε 18–42. (A) Snapshot of the 99 best structures provided by PepLook. (B) View of the best model of each population (Prime’s structure in pink and representative of 2^nd population in blue). (C) Local RMS (window of 9 residues) along the sequence. The reference structure is the Prime. The red plot represents the mean values of all models of the Prime’s subpopulation, the blue one represents the mean value for the all models of the second subpopulation. The standard deviations clearly indicate that the Prime’s populations are homogenous and that the second population is less homogenous. Taken from [87].