title: A gatekeeper helix determines the substrate specificity of Sjögren-Larsson Syndrome enzyme fatty aldehyde dehydrogenase.
abstract: Mutations in the gene coding for membrane-bound fatty aldehyde dehydrogenase (FALDH) lead to toxic accumulation of lipid species and development of the Sjögren-Larsson Syndrome (SLS), a rare disorder characterized by skin defects and mental retardation. Here, we present the crystallographic structure of human FALDH, the first model of a membrane-associated aldehyde dehydrogenase. The dimeric FALDH displays a previously unrecognized element in its C-terminal region, a 'gatekeeper' helix, which extends over the adjacent subunit, controlling the access to the substrate cavity and helping orientate both substrate cavities towards the membrane surface for efficient substrate transit between membranes and catalytic site. Activity assays demonstrate that the gatekeeper helix is important for directing the substrate specificity of FALDH towards long-chain fatty aldehydes. The gatekeeper feature is conserved across membrane-associated aldehyde dehydrogenases. Finally, we provide insight into the previously elusive molecular basis of SLS-causing mutations.
authors.affiliation: 1] Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innrain 80-82, 6020 Innsbruck, Austria [2] Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis court Rd, Cambridge CB2 1GA, UK.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Keller
authors.affiliation: European Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, 38042 Grenoble, France.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zander
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Julian E
authors.initials: JE
authors.lastname: Fuchs
authors.affiliation: Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kreutz
authors.affiliation: Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Watschinger
authors.affiliation: Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
authors.affiliation: Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Golderer
authors.affiliation: Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
authors.affiliation: 1] Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis court Rd, Cambridge CB2 1GA, UK [2] MRC National Institute for Medical Research, the Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Markus
authors.initials: M
authors.lastname: Ralser
authors.affiliation: Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kräutler
authors.affiliation: 1] Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innrain 80-82, 6020 Innsbruck, Austria [2].
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Werner
authors.affiliation: 1] European Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, 38042 Grenoble, France [2] Unit of Virus Host-Cell Interactions, University of Grenoble Alpes-EMBL-CNRS, 6 rue Jules Horowitz, 38042 Grenoble, France [3].
authors.forename: Jose A
authors.initials: JA
authors.lastname: Marquez
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D055503:Protein Multimerization; D016111:Sjogren-Larsson Syndrome / Q000201:enzymology* / Q000235:genetics; D013379:Substrate Specificity
chemical_list: D000445:Aldehyde Oxidoreductases; C038828:long-chain-aldehyde dehydrogenase