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J Biol Chem, Vol. 273, Issue 27, 17243-17250, July 3, 1998
From the Department of Molecular Genetics, University of Texas
Southwestern Medical Center, Dallas, Texas 75235
The NH2-terminal fragments of
sterol regulatory element-binding proteins (SREBPs) are released from
endoplasmic reticulum membranes by proteases whose activities depend
upon SREBP cleavage-activating protein (SCAP), a polytopic endoplasmic
reticulum membrane protein. The activity of SCAP is inhibited by
sterols, which appear to interact with the polytopic membrane domain of
SCAP. Here, we use protease protection and N-linked
glycosylation site-mapping techniques to define the topology of the
eight membrane-spanning domains of SCAP. The data indicate that the
NH2 terminus and COOH terminus of SCAP face the cytosol.
The long intralumenal loops after membrane-spanning segments 1 and 7 are glycosylated, confirming their lumenal location. The region
comprising membrane-spanning segments 2-6 shows sequence resemblance
to putative sterol-sensing domains in three other proteins:
3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), the
Niemann-Pick C1 protein, and the morphogen receptor Patched. The
orientation of the eight membrane-spanning segments in SCAP is
consistent with the model proposed for HMG-CoA reductase (Olender,
E. H., and Simoni, R. D. (1992) J. Biol.
Chem. 267, 4223-4235). The membrane-spanning domains of SCAP and
HMG-CoA reductase confer sterol sensitivity upon the functional
activities of the two molecules. The common membrane topology of the
two proteins is consistent with the notion that sterols regulate both proteins by a common mechanism.
Topology of SREBP Cleavage-activating Protein, a Polytopic
Membrane Protein with a Sterol-sensing Domain
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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