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PDBsum entry 4zr0
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Oxidoreductase
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PDB id
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4zr0
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References listed in PDB file
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Key reference
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Title
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The crystal structure of an integral membrane fatty acid α-Hydroxylase.
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Authors
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G.Zhu,
M.Koszelak-Rosenblum,
S.M.Connelly,
M.E.Dumont,
M.G.Malkowski.
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Ref.
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J Biol Chem, 2015,
290,
29820-29833.
[DOI no: ]
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PubMed id
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Abstract
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Neuronal electrical impulse propagation is facilitated by the myelin sheath, a
compact membrane surrounding the axon. The myelin sheath is highly enriched in
galactosylceramide (GalCer) and its sulfated derivative sulfatide. Over 50% of
GalCer and sulfatide in myelin is hydroxylated by the integral membrane enzyme
fatty acid 2-hydroxylase (FA2H). GalCer hydroxylation contributes to the compact
nature of the myelin membrane, and mutations in FA2H result in debilitating
leukodystrophies and spastic paraparesis. We report here the 2.6 Å crystal
structure of sphingolipid α-hydroxylase (Scs7p), a yeast homolog of FA2H. The
Scs7p core is composed of a helical catalytic cap domain that sits atop four
transmembrane helices that anchor the enzyme in the endoplasmic reticulum. The
structure contains two zinc atoms coordinated by the side chains of 10 highly
conserved histidines within a dimetal center located near the plane of the
cytosolic membrane. We used a yeast genetic approach to confirm the important
role of the dimetal-binding histidines in catalysis and identified Tyr-322 and
Asp-323 as critical determinants involved in the hydroxylase reaction.
Examination of the Scs7p structure, coupled with molecular dynamics simulations,
allowed for the generation of a model of ceramide binding to Scs7p. Comparison
of the Scs7p structure and substrate-binding model to the structure of
steroyl-CoA desaturase revealed significant differences in the architecture of
the catalytic cap domain and location of the dimetal centers with respect to the
membrane. These observations provide insight into the different mechanisms of
substrate binding and recognition of substrates by the hydroxylase and
desaturase enzymes.
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