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

Keller MA, Zander U, Fuchs JE, Kreutz C, Watschinger K, Mueller T, Golderer G, Liedl KR, Ralser M, Kräutler B, Werner ER, Marquez JA - Nat Commun (2014)

Bottom Line: Here, we present the crystallographic structure of human FALDH, the first model of a membrane-associated aldehyde dehydrogenase.The gatekeeper feature is conserved across membrane-associated aldehyde dehydrogenases.Finally, we provide insight into the previously elusive molecular basis of SLS-causing mutations.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Role of FALDH in selected membrane lipid metabolic pathways.In cells, fatty aldehydes are produced during oxidative stress-induced lipid peroxidation2 and by enzymatic degradation of a series of lipids including sphingosine-1-phosphate3, plasmalogens8 and alkylglycerols such as the platelet-activating factor12. Impaired FALDH function has been shown to alter the metabolic profiles of connected pathways and can lead to the development of the SLS (red arrows)322.
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f1: Role of FALDH in selected membrane lipid metabolic pathways.In cells, fatty aldehydes are produced during oxidative stress-induced lipid peroxidation2 and by enzymatic degradation of a series of lipids including sphingosine-1-phosphate3, plasmalogens8 and alkylglycerols such as the platelet-activating factor12. Impaired FALDH function has been shown to alter the metabolic profiles of connected pathways and can lead to the development of the SLS (red arrows)322.

Mentions: FALDH plays an important detoxifying role in different lipid degrading pathways (Fig. 1). This includes the enzymatic degradation of sphingosine-1-phosphate, which is a ligand for five specific G protein-coupled receptors6, implicating sphingosine-1-phosphate into a series of cellular processes such as proliferation, growth, movement, survival and immunity7. Impaired FALDH function in CHO-K1 cells results in an abnormal sphingosine-1-phosphate metabolism3. FALDH also clears the products of ether lipids degradation such as platelet-activating factor and plasmalogens8, molecules that are used for inter and intracellular signalling9101112. In addition, FALDH has been shown to protect cells against oxidative stress-induced lipid peroxidation2 and its expression is regulated by proliferator-activated receptor alpha13.


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

Keller MA, Zander U, Fuchs JE, Kreutz C, Watschinger K, Mueller T, Golderer G, Liedl KR, Ralser M, Kräutler B, Werner ER, Marquez JA - Nat Commun (2014)

Role of FALDH in selected membrane lipid metabolic pathways.In cells, fatty aldehydes are produced during oxidative stress-induced lipid peroxidation2 and by enzymatic degradation of a series of lipids including sphingosine-1-phosphate3, plasmalogens8 and alkylglycerols such as the platelet-activating factor12. Impaired FALDH function has been shown to alter the metabolic profiles of connected pathways and can lead to the development of the SLS (red arrows)322.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109017&req=5

f1: Role of FALDH in selected membrane lipid metabolic pathways.In cells, fatty aldehydes are produced during oxidative stress-induced lipid peroxidation2 and by enzymatic degradation of a series of lipids including sphingosine-1-phosphate3, plasmalogens8 and alkylglycerols such as the platelet-activating factor12. Impaired FALDH function has been shown to alter the metabolic profiles of connected pathways and can lead to the development of the SLS (red arrows)322.
Mentions: FALDH plays an important detoxifying role in different lipid degrading pathways (Fig. 1). This includes the enzymatic degradation of sphingosine-1-phosphate, which is a ligand for five specific G protein-coupled receptors6, implicating sphingosine-1-phosphate into a series of cellular processes such as proliferation, growth, movement, survival and immunity7. Impaired FALDH function in CHO-K1 cells results in an abnormal sphingosine-1-phosphate metabolism3. FALDH also clears the products of ether lipids degradation such as platelet-activating factor and plasmalogens8, molecules that are used for inter and intracellular signalling9101112. In addition, FALDH has been shown to protect cells against oxidative stress-induced lipid peroxidation2 and its expression is regulated by proliferator-activated receptor alpha13.

Bottom Line: Here, we present the crystallographic structure of human FALDH, the first model of a membrane-associated aldehyde dehydrogenase.The gatekeeper feature is conserved across membrane-associated aldehyde dehydrogenases.Finally, we provide insight into the previously elusive molecular basis of SLS-causing mutations.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus