title: Sphingosine Kinases: Emerging Structure-Function Insights.
abstract: Sphingosine kinases (SK1 and SK2) catalyse the conversion of sphingosine into sphingosine 1-phosphate and control fundamental cellular processes, including cell survival, proliferation, differentiation, migration, and immune function. In this review, we highlight recent breakthroughs in the structural and functional characterisation of SK1 and these are contextualised by analysis of crystal structures for closely related prokaryotic lipid kinases. We identify a putative dimerisation interface and propose novel regulatory mechanisms governing structural plasticity induced by phosphorylation and interaction with phospholipids and proteins. Our analysis suggests that the catalytic function and regulation of the enzymes might be dependent on conformational mobility and it provides a roadmap for future interrogation of SK1 function and its role in physiology and disease.
authors.affiliation: Institute of Chemical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, Scotland, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral St, Glasgow, G4 0RE, Scotland, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral St, Glasgow, G4 0RE, Scotland, UK. Electronic address: n.j.pyne@strath.ac.uk.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
mesh_terms: D017398:Alternative Splicing; D020816:Amino Acid Motifs; D020134:Catalytic Domain; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008246:Lysophospholipids / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000099157:Sphingosine Kinase
chemical_list: D007527:Isoenzymes; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C000594250:sphingosine kinase 2, human
keywords: DAGK_cat; SK2); TRAF2; diacylglycerol kinase (DGK); membrane curvature; sphingosine kinase (SK1