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Molecular Basis of Sphingosine Kinase 1 Substrate Recognition and Catalysis Structure Article Molecular Basis of Sphingosine Kinase 1 Substrate Recognition and Catalysis Zhulun Wang,1,* Xiaoshan Min,1 Shou-Hua Xiao,2 Sheree Johnstone,1 William Romanow,1 David Meininger,1 Haoda Xu,1 Jinsong Liu,1 Jessica Dai,2 Songzhu An,2 Stephen Thibault,1 and Nigel Walker1,* 1Department of Molecular Structure and Characterization 2Department of Oncology Research Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA *Correspondence: [email protected] (Z.W.), [email protected] (N.W.) http://dx.doi.org/10.1016/j.str.2013.02.025 SUMMARY (Kohama et al., 1998; Taha et al., 2006). They do not share sequence homology with other lipid kinases, such as phosphati- Sphingosine kinase 1 (SphK1) is a lipid kinase that dylinositol-3 kinase (PI3K). Five conserved domains (C1–C5) catalyzes the conversion of sphingosine to sphingo- have been identified within SphKs, with C1–C3 and C5 sharing sine-1-phosphate (S1P), which has been shown to homology with diacylglycerol kinase (DGK) and ceramide kinase, play a role in lymphocyte trafficking, angiogenesis, and C4 being unique for SphKs. Two mammalian isoforms known and response to apoptotic stimuli. As a central as SphK1 and SphK2 have been characterized (Kohama et al., enzyme in modulating the S1P levels in cells, 1998; Liu et al., 2000; Melendez et al., 2000; Nava et al., 2000; Oli- vera et al., 1998; Pitson et al., 2000). Although SphK1 and SphK2 SphK1 emerges as an important regulator for diverse catalyze the same biochemical reactions, they originate from cellular functions and a potential target for drug different genes and present different substrate specificities, tis- discovery. Here, we present the crystal structures sue distributions, and subcellular localization patterns (Liu of human SphK1 in the apo form and in complexes et al., 2003; Maceyka et al., 2005; Taha et al., 2006). Interestingly, with a substrate sphingosine-like lipid, ADP, and an knockout studies show that mice lacking either SphK1 or SphK2 inhibitor at 2.0–2.3 A˚ resolution. The SphK1 struc- were viable and fertile and had no obvious abnormality (Allende tures reveal a two-domain architecture in which its et al., 2004; Mizugishi et al., 2005). However, deletion of both catalytic site is located in the cleft between the two these genes in mice proved to be lethal to the embryo, which ex- domains and a hydrophobic lipid-binding pocket hibited severe defects in neurogenesis and angiogenesis (Mizu- is buried in the C-terminal domain. Comparative gishi et al., 2005). These studies suggest that SphK1 and analysis of these structures with mutagenesis and SphK2 have at least some functional redundancy. SphK1 has intrinsic catalytic activity, but it can be further acti- kinetic studies provides insight into how SphK1 vated by a range of membrane receptors and signaling mole- recognizes the lipid substrate and catalyzes ATP- cules. These include G protein coupled receptors (GPCRs), dependent phosphorylation. growth factors, proinflammatory cytokines, and hormones, which stimulate SphK1, leading to a rapid increase in S1P levels INTRODUCTION that in-turn modulates a number of signaling pathways (Hannun and Obeid, 2008; Pan et al., 2011; Spiegel and Milstien, 2003). In Sphingolipids are important bioactive lipid signaling molecules in addition to agonist activation, localization of SphK1 appears to the regulation of many cellular processes (Hannun and Obeid, be another factor critical to its production of S1P that mediates 2008; Ponnusamy et al., 2010). Among them, sphingosine-1- the downstream signaling function (Wattenberg et al., 2006). phosphate (S1P) has emerged as a crucial player in various Phosphorylation at Ser225 of SphK1 by extracellular-signal- physiological processes, including cancer and inflammation regulated kinase (ERK1/2) not only increases SphK1 activity, (Beaven, 2007; Brinkmann et al., 2010; Maceyka et al., 2012; but also promotes translocation of SphK1 from the cytoplasm Pyne and Pyne, 2010; Pyne et al., 2012a). A broad spectrum of to the plasma membrane (Pitson et al., 2003, 2005). Thus, the roles has been established for this pleiotropic phospholipid. biology behind SphK1 action is multifaceted. S1P has been shown to play a vital role in diverse biological pro- Elevated expression of SphK1 is observed in a wide range of cesses, including lymphocyte trafficking, cell growth, apoptosis, cancers, including solid tumors of the breast, colon, lung, ovary, mitogenesis, chemosensitization, and angiogenesis (Chi, 2011; stomach, uterus, kidney, and rectum, as well as in leukemia Cuvillier et al., 1996; English et al., 1999; Hannun and Obeid, (Alshaker et al., 2013; Heffernan-Stroud and Obeid, 2013). Upre- 2008; Kihara et al., 2007; Olivera and Spiegel, 1993; Rosen gulation of SphK1 has been associated with tumor angiogenesis and Goetzl, 2005; Spiegel and Milstien, 2011; Strub et al., 2010). or lymphangiogenesis and with radiation or chemotherapy resis- S1P is generated by the action of sphingosine kinases (SphKs), tance and sensitivity (Gault and Obeid, 2011; Pitman and Pitson, which catalyze the ATP-dependent phosphorylation of sphingo- 2010; Pyne et al., 2012b; Shida et al., 2008). Hence, SphK1 sine on its primary hydroxyl group. SphKs constitute a distinct presents a promising novel molecular target for therapeutic class of lipid kinase family that is evolutionarily highly conserved intervention in cancer and inflammatory diseases (Antoon 798 Structure 21, 798–809, May 7, 2013 ª2013 Elsevier Ltd All rights reserved Structure Molecular Basis of Sphingosine Kinase 1 Regulation Table 1. X-ray Data Collection and Refinement Statistics Data Collection Native Phasing SeMet-SphK1 (MAD) Data set ‘‘apo’’ SKI-II SKI-II+ADP Peak Edge High Remote Low Remote Space group C2221 P212121 P212121 C2221 Cell Dimensions a (A˚ ) 101.8 102.2 102.2 101.96 101.7 101.7 101.7 b (A˚ ) 226.2 106.6 106.6 229.4 228.2 227.8 227.7 c (A˚ ) 106.5 226.1 226.0 107.1 106.8 106.7 106.7 Wavelength (A˚ ) 1.000 1.0 1.0 0.9792 0.9793 0.9641 1.000 Resolution (A˚ ) 50–2.0 (2.11–2.0) 50–2.3 (2.42–2.3) 96–2.3 (2.42–2.3) 50–2.8 50–2.8 50–2.8 50–2.8 (2.9–2.8) (2.9–2.8) (2.9–2.8) (2.9–2.8) Completeness (%) 99.7 (97.9) 91.9 (85.7) 98.6 (97.1) 98.6 (88.2) 100 (100) 100 (100) 99.7 (98.4) Average I/s (I) 13.2 (2.5) 12.2 (3.1) 13.5 (2.9) 34.2 (3.0) 56 (12) 41 (7.6) 25.3 (3.8) No. of unique reflections 82,863 (11,784) 101,561 (13,635) 108,671 (15,455) 30,780 30,883 30,549 31,304 (2,722) (3,043) (3,021) (3,063) Redundancy 3.5 (3.5) 3.4 (3.4) 3.6 (3.5) 13.2 (7.4) 14.6 (14.7) 9.8 (9.8) 4.1 (4.0) a Rmerge (%) 6.2 (48.8) 5.7 (38.1) 6.5 (36.8) 9.9 6.6 6.5 5.2 Refinement Resolution range (A˚ ) 50–2.0 (2.11–2.0) 50–2.3 (2.42–2.3) 50–2.3 (2.42–2.3) Number of Atoms Protein 8,159 16,052 16,216 Solvent 382 292 358 Ligands 108 128 209 Average B-Factor (A˚ 2 ) Protein 38.7 43.9 38.8 Ligand 53.5 51.2 43.0 Solvent 41.5 38.0 35.7 R factorb 21.6 22.9 20.6 c Rfree 26.4 28.5 26.9 rmsd bond lengths (A˚ ) 0.008 0.010 0.020 rmsd bond angles () 1.35 1.46 2.04 Values in parentheses refer to statistics in the highest-resolution shell. rmsd, root-mean-square deviation. a Rmerge = SjIobs À <I> j/SIobs. b R factor = SjFobs À Fcalcj/SFobs, where Fobs and Fcalc are the observed and calculated structure-factor amplitudes, respectively. c Rfree was computed using 5% of the data assigned randomly. and Beckman, 2011; Orr Gandy and Obeid, 2013; Takabe et al., active (Figure S1 available online). The protein purified from the 2008). Whereas the importance of SphK1 activity is well baculovirus expression system has been crystallized both in established in several human pathologies, understanding the the apo form and in the presence of various combinations of molecular basis of SphK1 activation has been hampered by ATP and its analogs, substrate/product as well as inhibitors. the lack of three-dimensional crystal structure data for any The crystal structure of apo SphK1 was determined first by the of the SphKs. Here, we present a crystal structure of human multiwavelength anomalous dispersion (MAD) method using SphK1 at 2.0 A˚ resolution without any added ligands. Moreover, crystals grown from selenomethionyl-enriched protein and ˚ we have solved the SphK1 structures in the presence of an inhib- refined at 2.0 A resolution in the space group C2221. There are itor and an inhibitor plus ADP, at 2.3 A˚ resolution in both cases. three molecules in the asymmetric unit, which are highly similar. The final electron density maps are of high quality throughout the RESULTS protein (residues 9–364) for one molecule, and of good quality for the other two protein molecules, which have a few disordered Structure Determination loop regions, including residues 186–187, 219–231, and 333– Since the full-length recombinant human SphK1 protein failed 335. The cocrystal structures of SphK1 in complex with an to produce crystals, we generated a panel of protein con- SphK inhibitor, SKI-II (French et al., 2003, 2006), and in complex structs with a combination of N-terminal and C-terminal trunca- with ADP and SKI-II were solved by molecular replacement, in ˚ tions to search for a soluble and crystallizable protein.
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