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J. Biol. Chem., Vol. 276, Issue 21, 18407-18414, May 25, 2001
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From the Atlantic Research Centre, Departments of Pediatrics and
Biochemistry and Molecular Biology, IWK Health Centre, Dalhousie
University, Halifax, Nova Scotia B3H 4H7, Canada
Oxysterol-binding proteins (OSBPs)
are a family of eukaryotic intracellular lipid receptors. Mammalian
OSBP1 binds oxygenated derivatives of cholesterol and mediates sterol
and phospholipid synthesis through as yet poorly undefined mechanisms.
The precise cellular roles for the remaining members of the
oxysterol-binding protein family remain to be elucidated. In yeast, a
family of OSBPs has been identified based on primary sequence
similarity to the ligand binding domain of mammalian OSBP1. Yeast
Kes1p, an oxysterol-binding protein family member that consists of only the ligand binding domain, has been demonstrated to regulate the Sec14p
pathway for Golgi-derived vesicle transport. Specifically, inactivation
of the KES1 gene resulted in the ability of yeast to
survive in the absence of Sec14p, a
phosphatidylinositol/phosphatidylcholine transfer protein that is
normally required for cell viability due to its essential requirement
in transporting vesicles from the Golgi. We cloned the two human
members of the OSBP family, ORP1 and ORP2, with the highest degree of
similarity to yeast Kes1p. We expressed ORP1 and ORP2 in yeast lacking
Sec14p and Kes1p function and found that ORP1 complemented Kes1p
function with respect to cell growth and Golgi vesicle transport,
whereas ORP2 was unable to do so. Phenotypes associated with
overexpression of ORP2 in yeast were a dramatic decrease in cell growth
and a block in Golgi-derived vesicle transport distinct from that of ORP1. Purification of ORP1 and ORP2 for ligand binding studies demonstrated ORP1 and ORP2 did not bind 25-hydroxycholesterol but
instead bound phospholipids with both proteins exhibiting strong
binding to phosphatidic acid and weak binding to phosphatidylinositol 3-phosphate. In Chinese hamster ovary cells, ORP1 localized to a
cytosolic location, whereas ORP2 was associated with the Golgi apparatus, consistent with our vesicle transport studies that indicated
ORP1 and ORP2 function at different steps in the regulation of
vesicle transport.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF274714 and AY028168.
Novel Members of the Human Oxysterol-binding Protein Family Bind
Phospholipids and Regulate Vesicle Transport*
§,
*
This work was supported by Canadian Institutes of Health
Research operating grant and scholarship (to C. R. M.), a Canadian Institutes of Health Research/Rx&D (Glaxo Wellcome and Smith
Kline & French Laboratories) fellowship (to Y. X.), a Heart and Stroke Foundation of Canada operating grant, and a Canadian Institutes of
Health Research scientist award (to N. D. R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Dept. of Cell Biology and Anatomy, University of
Calgary, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada.
§
Both authors contributed equally to this work.
¶
To whom correspondence should be addressed. Tel.:
902-494-7066; Fax: 902-494-1394; E-mail: cmcmaste@is.dal.ca.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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