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| | ==Structure of the Human Sjogren Larsson Syndrome enzyme fatty aldehyde dehydrogenase (FALDH)== | | ==Structure of the Human Sjogren Larsson Syndrome enzyme fatty aldehyde dehydrogenase (FALDH)== |
| - | <StructureSection load='4qgk' size='340' side='right' caption='[[4qgk]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4qgk' size='340' side='right'caption='[[4qgk]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4qgk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QGK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QGK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4qgk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QGK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QGK FirstGlance]. <br> |
| - | </td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Aldehyde_dehydrogenase_(NAD(+)) Aldehyde dehydrogenase (NAD(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.1.3 1.2.1.3] </span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qgk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qgk OCA], [http://pdbe.org/4qgk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qgk RCSB], [http://www.ebi.ac.uk/pdbsum/4qgk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qgk ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4qgk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qgk OCA], [https://pdbe.org/4qgk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qgk RCSB], [https://www.ebi.ac.uk/pdbsum/4qgk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qgk ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/AL3A2_HUMAN AL3A2_HUMAN]] Sjogren-Larsson syndrome. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:8528251</ref> <ref>PMID:9254849</ref> <ref>PMID:9829906</ref> <ref>PMID:10577908</ref> <ref>PMID:10792573</ref> | + | [https://www.uniprot.org/uniprot/AL3A2_HUMAN AL3A2_HUMAN] Sjogren-Larsson syndrome. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:8528251</ref> <ref>PMID:9254849</ref> <ref>PMID:9829906</ref> <ref>PMID:10577908</ref> <ref>PMID:10792573</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AL3A2_HUMAN AL3A2_HUMAN]] Catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acids. Active on a variety of saturated and unsaturated aliphatic aldehydes between 6 and 24 carbons in length. Responsible for conversion of the sphingosine 1-phosphate (S1P) degradation product hexadecenal to hexadecenoic acid.<ref>PMID:22633490</ref> | + | [https://www.uniprot.org/uniprot/AL3A2_HUMAN AL3A2_HUMAN] Catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acids. Active on a variety of saturated and unsaturated aliphatic aldehydes between 6 and 24 carbons in length. Responsible for conversion of the sphingosine 1-phosphate (S1P) degradation product hexadecenal to hexadecenoic acid.<ref>PMID:22633490</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Mutations in the gene coding for membrane-bound fatty aldehyde dehydrogenase (FALDH) lead to toxic accumulation of lipid species and development of the Sjogren-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. |
| | + | |
| | + | A gatekeeper helix determines the substrate specificity of Sjogren-Larsson Syndrome enzyme fatty aldehyde dehydrogenase.,Keller MA, Zander U, Fuchs JE, Kreutz C, Watschinger K, Mueller T, Golderer G, Liedl KR, Ralser M, Krautler B, Werner ER, Marquez JA Nat Commun. 2014 Jul 22;5:4439. doi: 10.1038/ncomms5439. PMID:25047030<ref>PMID:25047030</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 4qgk" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Aldehyde dehydrogenase|Aldehyde dehydrogenase]] | + | *[[Aldehyde dehydrogenase 3D structures|Aldehyde dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Keller, M]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Marquez, J A]] | + | [[Category: Large Structures]] |
| - | [[Category: Zander, U]] | + | [[Category: Keller M]] |
| - | [[Category: Aldehyde dehydrogenase]] | + | [[Category: Marquez JA]] |
| - | [[Category: Fatty aldehyde dehydrogenase]] | + | [[Category: Zander U]] |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Sjogren larsson syndrome]]
| + | |
| Structural highlights
Disease
AL3A2_HUMAN Sjogren-Larsson syndrome. The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] [5]
Function
AL3A2_HUMAN Catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acids. Active on a variety of saturated and unsaturated aliphatic aldehydes between 6 and 24 carbons in length. Responsible for conversion of the sphingosine 1-phosphate (S1P) degradation product hexadecenal to hexadecenoic acid.[6]
Publication Abstract from PubMed
Mutations in the gene coding for membrane-bound fatty aldehyde dehydrogenase (FALDH) lead to toxic accumulation of lipid species and development of the Sjogren-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.
A gatekeeper helix determines the substrate specificity of Sjogren-Larsson Syndrome enzyme fatty aldehyde dehydrogenase.,Keller MA, Zander U, Fuchs JE, Kreutz C, Watschinger K, Mueller T, Golderer G, Liedl KR, Ralser M, Krautler B, Werner ER, Marquez JA Nat Commun. 2014 Jul 22;5:4439. doi: 10.1038/ncomms5439. PMID:25047030[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ De Laurenzi V, Rogers GR, Hamrock DJ, Marekov LN, Steinert PM, Compton JG, Markova N, Rizzo WB. Sjogren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nat Genet. 1996 Jan;12(1):52-7. PMID:8528251 doi:http://dx.doi.org/10.1038/ng0196-52
- ↑ Sillen A, Jagell S, Wadelius C. A missense mutation in the FALDH gene identified in Sjogren-Larsson syndrome patients originating from the northern part of Sweden. Hum Genet. 1997 Aug;100(2):201-3. PMID:9254849
- ↑ Sillen A, Anton-Lamprecht I, Braun-Quentin C, Kraus CS, Sayli BS, Ayuso C, Jagell S, Kuster W, Wadelius C. Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjogren-Larsson syndrome. Hum Mutat. 1998;12(6):377-84. PMID:9829906 doi:<377::AID-HUMU3>3.0.CO;2-I http://dx.doi.org/10.1002/(SICI)1098-1004(1998)12:6<377::AID-HUMU3>3.0.CO;2-I
- ↑ Rizzo WB, Carney G, Lin Z. The molecular basis of Sjogren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene. Am J Hum Genet. 1999 Dec;65(6):1547-60. PMID:10577908 doi:http://dx.doi.org/S0002-9297(07)63574-5
- ↑ Aoki N, Suzuki H, Ito K, Ito M. A novel point mutation of the FALDH gene in a Japanese family with Sjogren-Larsson syndrome. J Invest Dermatol. 2000 May;114(5):1065-6. PMID:10792573 doi:http://dx.doi.org/10.1046/j.1523-1747.2000.00960-5.x
- ↑ Nakahara K, Ohkuni A, Kitamura T, Abe K, Naganuma T, Ohno Y, Zoeller RA, Kihara A. The Sjogren-Larsson syndrome gene encodes a hexadecenal dehydrogenase of the sphingosine 1-phosphate degradation pathway. Mol Cell. 2012 May 25;46(4):461-71. doi: 10.1016/j.molcel.2012.04.033. PMID:22633490 doi:http://dx.doi.org/10.1016/j.molcel.2012.04.033
- ↑ Keller MA, Zander U, Fuchs JE, Kreutz C, Watschinger K, Mueller T, Golderer G, Liedl KR, Ralser M, Krautler B, Werner ER, Marquez JA. A gatekeeper helix determines the substrate specificity of Sjogren-Larsson Syndrome enzyme fatty aldehyde dehydrogenase. Nat Commun. 2014 Jul 22;5:4439. doi: 10.1038/ncomms5439. PMID:25047030 doi:http://dx.doi.org/10.1038/ncomms5439
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