4qgk

From Proteopedia

Structure of the Human Sjogren Larsson Syndrome enzyme fatty aldehyde dehydrogenase (FALDH)

PDB ID 4qgk

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Structural highlights

4qgk is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.1Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

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