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Sökning: id:"swepub:oai:DiVA.org:uu-406464" > Binding and intrace...

Binding and intracellular transport of 25-hydroxycholesterol by Niemann-Pick C2 protein

Petersen, Daniel (författare)
Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark.
Reinholdt, Peter (författare)
Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.
Szomek, Maria (författare)
Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark.
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Hansen, Selina Kruuse (författare)
Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark.
Poongavanam, Vasanthanathan (författare)
Uppsala universitet,Organisk kemi,Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.
Dupont, Alice (författare)
Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark.
Heegaard, Christian W. (författare)
Univ Aarhus, Dept Mol Biol & Genet, DK-8000 Aarhus C, Denmark.
Krishnan, Kathiresan (författare)
Washington Univ, Dept Dev Biol, St Louis, MO 63110 USA.
Fujiwara, Hideji (författare)
Washington Univ, Dept Dev Biol, St Louis, MO 63110 USA.
Covey, Douglas F. (författare)
Washington Univ, Dept Dev Biol, St Louis, MO 63110 USA.; Washington Univ, Taylor Family Inst Innovat Psychiat Res, St Louis, MO 63110 USA.
Ory, Daniel S. (författare)
Washington Univ, Dept Med, St Louis, MO 63110 USA.
Kongsted, Jacob (författare)
Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.
Wustner, Daniel (författare)
Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark.
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Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark. (creator_code:org_t)
Elsevier BV, 2020
2020
Engelska.
Ingår i: Biochimica et Biophysica Acta - Biomembranes. - : Elsevier BV. - 0005-2736 .- 1879-2642. ; 1862:2
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • Side-chain oxidized cholesterol derivatives, like 25-hydroxycholesterol (25-OH-Chol) are important regulators of cellular cholesterol homeostasis. How transport of oxysterols through the endo-lysosomal pathway contributes to their biological function is not clear. The Niemann-Pick C2 protein (NPC2) is a small lysosomal sterol transfer protein required for export of cholesterol from late endosomes and lysosomes (LE/LYSs). Here, we show that 25-hydroxy-cholestatrienol, (25-OH-CTL), an intrinsically fluorescent analogue of 25-OH-Chol, becomes trapped in LE/LYSs of NPC2-deficient fibroblasts, but can efflux from the cells even in the absence of NPC2 upon removal of the sterol source. Fluorescence recovery after photobleaching (FRAP) of 25-OH-CTL in endo-lysosomes was rapid and extensive and only partially dependent on NPC2 function. Using quenching of NPC2's intrinsic fluorescence, we show that 25-OH-Chol and 25-OH-CTL can bind to NPC2 though with lower affinity compared to cholesterol and its fluorescent analogues, cholestatrienol (CTL) and dehydroergosterol (DHE). This is confirmed by calculations of binding energies which additionally show that 25-OH-CTL can bind in two orientations to NPC2, in stark contrast to cholesterol and its analogues. We conclude that NPC2's affinity for all sterols is energetically favored over their self-aggregation in the lysosomal lumen. Lysosomal export of 25-OH-Chol is not strictly dependent on the NPC2 protein.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Nyckelord

Binding
Fluorescence
Lysosome
Free energy calculation
Electronic structure calculation

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