br Sphingosine kinase One of the
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 AZD1152-HQPA 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).
PIK superfamily: model of PI3Kα (p110α/p85α complex) Phosphoinositide lipid kinases (PIKs) are enzymes that catalyze the generation of specific phosphorylated variants of phosphatidylinositols (PtdIns) (Fruman et al., 1998). This superfamily of lipid kinase can be further divided into three major families according to the position of the inositol ring that get phosphorylated: the PtIns 3-kinases (PI3Ks), PtdIns 4-kinases (PI4Ks), and PtdIns-P (PtdinP) kinases (PIP4K and PIP5K) (Brown and Auger, 2011). Among all the PIKs, the structure of PI3K have been studied intensively likely because it\'s central role in tumor biology (Braccini et al., 2015; Costa et al., 2018; Follo et al., 2015; Janku et al., 2018; Liu et al., 2018). PI3Ks are a family of lipid kinases capable of catalyzing the phosphorylation of the 3′-hydroxyl group of the inositol ring. Based on primary structure and regulatory domain similarity, PI3Ks are further grouped into three classes (Leevers et al., 1999). Here we just focus on PI3Kα, one member from class I, as an example to explore how the molecular structure of PIK is correlated to its specific catalytic mechanism. Unlike DGKB and SK1, which are homodimer and monomer in solution, respectively, PI3Kα is a heterodimer composed of an 85 kD regulatory subunit (p85α) and a 110 kD catalytic subunit (p110α). Each subunit contains 5 domains respectively as illustrated in Fig. 2A. p110α contains an adaptor-binding domain (ABD), a Ras-binding domain (RBD), a C2 domain, a helical domain, and a kinase domain (Amzel et al., 2008; Gabelli et al., 2010; Huang et al., 2007). p85 is composed of an SH3 domain, a GAP domain, an N-terminal SH2 (nSH2) domain, an inter-SH2 domain (iSH2), and a C-terminal SH2 domain (cSH2) (Gabelli et al., 2010; Huang et al., 2007). As the full-length structure of p110α/p85α complex is not available, a truncated enzymatic active complex p110α/niSH2, which contains full length of p110α and the nSH2/iSH2 domain of p85α was used to illustrate the organization of PI3Kα (Huang et al., 2007).