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    • While linear sequences are important they

    2020-07-28

    While linear sequences are important, they must be viewed with some caution. One noteworthy example is the C1 domains which have attracted some interest as they are known to bind phorbol esters and DAG (reviewed in (Das and Rahman, 2014)). In this, it was not unreasonable to suspect that one or more of the three C1 domains in DGK-θ is likely involved in binding catalytic DAG. The presence of these motifs, however, does not establish catalytic DAG binding. Hurley et al. analyzed 54 C1 domains including six DGKs (α, β, γ, ε, δ and ζ) and suggested that of these DGKs, only DGK-β and DGK-γ contained a C1 domain that fit a profile for phorbol ester binding (Hurley et al., 1997). Importantly, the C1 domains of DGK-θ, as well as DGKδ and η, do not bind DAG (Sakane et al., 1996; Shindo et al., 2001, 2003). The involvement of these domains in catalysis is further questioned by the observation that the drosophila DGK1 does not contain any C1 domains (Masai et al., 1992), and porcine DGK-α lacking its C1 domains retains catalytic activity with a DAG Km similar to the wild type enzyme (Sakane et al., 1996). As a result, while the C1 domains may contribute to membrane localization for some DGKs, the catalytic DAG binding site remains unresolved. While these domains are not likely to be involved in binding catalytic DAG, they may bind other serine threonine protein kinase or participate in protein-protein interactions as suggested by Shulga et al. (2011a). In support of this notion, the C1 domain of DGKζ has been shown to mediate interactions with β-arrestins (Nelson et al., 2007) and Rac1 (Yakubchyk et al., 2005). Finally, it is important to note that there is some evidence suggesting this domain may be involved in membrane association following the activation of some G-protein coupled receptors (van Baal et al., 2005). The RA and PR domains are also poorly understood. Binding energies derived from in silico analyses suggests that the RA domain of DGK-θ does not bind Ras (Kiel et al., 2005). DGK-θ binds to, and is inhibited by the GTP-bound form of another small GTPase, RhoA, but it is not clear whether RhoA specifically binds to the RA domain. As PR domain contains a pXPXXP motif (Yu et al., 1994), it is also tempting to suggest that they bind SH3-domain containing proteins.
    Sphingosine kinase One of the enzymes closely related to DGKs are the sphingosine kinases (SKs). These enzymes catalyze the conversion of sphingosine (Sph) to sphingosine-1-phosphate (S1P). SKs and DGKs are closely related lipid kinase in term of basic enzymology and the mechanism of regulation and the details are well summarized in (Raben and Wattenberg, 2009; Siow et al., 2015). While there are two SK isoforms, SK1 and SK2, structural information exists for SK1 only. SK1 and its catalytic product, S1P, have been found closely linked to breast cancer and become a new target for breast cancer treatment (Geffken and Spiegel, 2018). Similar to DgkB, SK1 harbors a two-domain architecture with a N-terminal ATP binding domain (NTD) and a C-terminal Sph binding domain (CTD), both maintain an αβ fold (Adams et al., 2016). The catalytic center is located in between the two domains, with a Asp81 assigned as the likely general base responsible for the deprotonation of Sph (Wang et al., 2013). The ATP binding site is highly homologous with the prokaryotic DgkB as illustrated in Fig. 1B and D. Unlike DgkB, SK1 has a well-known conserved lipid substrate binding site in the CTD that makes extensive surface contact with the Sph substrate and the access of Sph to the lipid binding site is likely mediated by the opening and closure of a lipid binding loop (Adams et al., 2016). In addition, similar to DgkB, SK1 has a putative dimerization interface through NTD-NTD interaction. This dimerization is thought to be functional important to extract the lipid substrate from membrane because it leads to the exposure of both lipid binding loop on SK1 to the membranes and at the same time, direct a positively charged concave surface in the dimer interface to the negatively charged membrane (Adams et al., 2016). Recently, Pulkoski-Gross et al. demonstrated that SK1 contains a positively charged and hydrophobic motifs together mediates the interaction of this enzyme with membranes (Pulkoski-Gross et al., 2018).