Author
Listed:
- Markus A. Keller
(Biocenter, Innsbruck Medical University
University of Cambridge)
- 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
MRC National Institute for Medical Research)
- 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
Unit of Virus Host-Cell Interactions, University of Grenoble Alpes-EMBL-CNRS)
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.
Suggested Citation
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 & Jo, 2014.
"A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase,"
Nature Communications, Nature, vol. 5(1), pages 1-12, December.
Handle:
RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5439
DOI: 10.1038/ncomms5439
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