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A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase
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 structur...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Pub. Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109017/ https://www.ncbi.nlm.nih.gov/pubmed/25047030 http://dx.doi.org/10.1038/ncomms5439 |
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author | Keller, Markus A. Zander, Ulrich Fuchs, Julian E. Kreutz, Christoph Watschinger, Katrin Mueller, Thomas Golderer, Georg Liedl, Klaus R. Ralser, Markus Kräutler, Bernhard Werner, Ernst R. Marquez, Jose A. |
author_facet | Keller, Markus A. Zander, Ulrich Fuchs, Julian E. Kreutz, Christoph Watschinger, Katrin Mueller, Thomas Golderer, Georg Liedl, Klaus R. Ralser, Markus Kräutler, Bernhard Werner, Ernst R. Marquez, Jose A. |
author_sort | Keller, Markus A. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4109017 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Pub. Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-41090172014-08-15 A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase Keller, Markus A. Zander, Ulrich Fuchs, Julian E. Kreutz, Christoph Watschinger, Katrin Mueller, Thomas Golderer, Georg Liedl, Klaus R. Ralser, Markus Kräutler, Bernhard Werner, Ernst R. Marquez, Jose A. Nat Commun Article 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. Nature Pub. Group 2014-07-22 /pmc/articles/PMC4109017/ /pubmed/25047030 http://dx.doi.org/10.1038/ncomms5439 Text en Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ |
spellingShingle | Article Keller, Markus A. Zander, Ulrich Fuchs, Julian E. Kreutz, Christoph Watschinger, Katrin Mueller, Thomas Golderer, Georg Liedl, Klaus R. Ralser, Markus Kräutler, Bernhard Werner, Ernst R. Marquez, Jose A. A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase |
title | A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase |
title_full | A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase |
title_fullStr | A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase |
title_full_unstemmed | A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase |
title_short | A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase |
title_sort | gatekeeper helix determines the substrate specificity of sjögren–larsson syndrome enzyme fatty aldehyde dehydrogenase |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109017/ https://www.ncbi.nlm.nih.gov/pubmed/25047030 http://dx.doi.org/10.1038/ncomms5439 |
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