Supernatant protein factor in complex with RRR-alpha-tocopherylquinone: a link between oxidized Vitamin E and cholesterol biosynthesis.
The vast majority of monomeric lipid transport in nature is performed by lipid-specific protein carriers. This class of proteins can enclose cognate lipid molecules in a hydrophobic cavity and transport them across the aqueous environment. Supernatant protein factor (SPF) is an enigmatic representative of monomeric lipid transporters belonging to the SEC14 family. SPF stimulates squalene epoxidation, a downstream step of the cholesterol biosynthetic pathway, by an unknown mechanism. Here, we present the three-dimensional crystal structure of human SPF in complex with RRR-alpha-tocopherylquinone, the major physiological oxidation product of RRR-alpha-tocopherol, at a resolution of 1.95A. The structure of the complex reveals how SPF sequesters RRR-alpha-tocopherylquinone (RRR-alpha-TQ) in its protein body and permits a comparison with the recently solved structure of human alpha-tocopherol transfer protein (alpha-TTP) in complex with RRR-alpha-tocopherol. Recent findings have shown that RRR-alpha-TQ is reduced in vivo to RRR-alpha-TQH(2), the latter has been suggested to protect low-density lipoprotein (LDL) particles from oxidation. Hence, the antioxidant function of the redox couple RRR-alpha-TQ/RRR-alpha-TQH(2) in blocking LDL oxidation may reduce cellular cholesterol uptake and thus explain how SPF upregulates cholesterol synthesis.
Stocker
Achim
A
Department of Chemistry and Biochemistry, University of Berne, 3012 Bern, Switzerland. achim.stocker@ibc.unibe.ch
Baumann
Ulrich
U
D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis*; D018360:Crystallography, X-Ray; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D015534:Trans-Activators; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000737:chemistry* / Q000378:metabolism
D000975:Antioxidants; D002352:Carrier Proteins; D008074:Lipoproteins; C432422:SEC14L2 protein, human; D015534:Trans-Activators; D014810:Vitamin E; C002421:tocopherylquinone; D002784:Cholesterol