A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase

Markus A. Keller (), Ulrich Zander, Julian E. Fuchs, Christoph Kreutz, Katrin Watschinger, Thomas Mueller, Georg Golderer, Klaus R. Liedl, Markus Ralser, Bernhard Kräutler, Ernst R. Werner and Jose A. Marquez ()
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Markus A. Keller: Biocenter, Innsbruck Medical University
Ulrich Zander: European Molecular Biology Laboratory, Grenoble Outstation
Julian E. Fuchs: Institute of General, Inorganic and Theoretical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck
Christoph Kreutz: Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck
Katrin Watschinger: Biocenter, Innsbruck Medical University
Thomas Mueller: Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck
Georg Golderer: Biocenter, Innsbruck Medical University
Klaus R. Liedl: Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck
Markus Ralser: University of Cambridge
Bernhard Kräutler: Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck
Ernst R. Werner: Biocenter, Innsbruck Medical University
Jose A. Marquez: European Molecular Biology Laboratory, Grenoble Outstation

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5439

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