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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

Point mutations causative for the SLS and affected residues in the FALDH structure.The FALDH backbone is shown in white cartoon representation. Residues affected by SLS-causing mutations are shown in ball and stick representation and were coloured according to the assumed molecular implication. Orange, mutations leading to protein misfolding (19). Green, mutations at the dimerization interface (8). Red, mutations affecting the catalytic site (5). Blue, special mutations (3). For a detailed list, see Supplementary Table 1.
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f6: Point mutations causative for the SLS and affected residues in the FALDH structure.The FALDH backbone is shown in white cartoon representation. Residues affected by SLS-causing mutations are shown in ball and stick representation and were coloured according to the assumed molecular implication. Orange, mutations leading to protein misfolding (19). Green, mutations at the dimerization interface (8). Red, mutations affecting the catalytic site (5). Blue, special mutations (3). For a detailed list, see Supplementary Table 1.

Mentions: Using the novel structural information, we investigated the molecular mechanism of missense mutations known to cause SLS. We classified the mutations according to their expected effects on the active site (Fig. 6, red), dimerization (Fig. 6, green), protein misfolding (Fig. 6, orange) and special mutations (Fig. 6, blue). The effect on protein stability was estimated by calculating ΔΔG values with the empirical FoldX force field (Methods). A detailed list of all mutations can be found in Supplementary Table 1.


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)

Point mutations causative for the SLS and affected residues in the FALDH structure.The FALDH backbone is shown in white cartoon representation. Residues affected by SLS-causing mutations are shown in ball and stick representation and were coloured according to the assumed molecular implication. Orange, mutations leading to protein misfolding (19). Green, mutations at the dimerization interface (8). Red, mutations affecting the catalytic site (5). Blue, special mutations (3). For a detailed list, see Supplementary Table 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Point mutations causative for the SLS and affected residues in the FALDH structure.The FALDH backbone is shown in white cartoon representation. Residues affected by SLS-causing mutations are shown in ball and stick representation and were coloured according to the assumed molecular implication. Orange, mutations leading to protein misfolding (19). Green, mutations at the dimerization interface (8). Red, mutations affecting the catalytic site (5). Blue, special mutations (3). For a detailed list, see Supplementary Table 1.
Mentions: Using the novel structural information, we investigated the molecular mechanism of missense mutations known to cause SLS. We classified the mutations according to their expected effects on the active site (Fig. 6, red), dimerization (Fig. 6, green), protein misfolding (Fig. 6, orange) and special mutations (Fig. 6, blue). The effect on protein stability was estimated by calculating ΔΔG values with the empirical FoldX force field (Methods). A detailed list of all mutations can be found in Supplementary Table 1.

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