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J. Biol. Chem., Vol. 276, Issue 25, 22788-22796, June 22, 2001
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From the Department of Medical Biochemistry, University of Aarhus,
DK-8000, Aarhus C, Denmark
We previously isolated and sequenced the
~250-kDa type 1 receptor sorLA/LR11, a mosaic protein with elements
characterizing the Vps10p domain receptor family as well as the low
density lipoprotein receptor family. The N terminus of the Vps10p
domain comprises a consensus sequence for cleavage by furin
(50RRKR53) that precedes a truncation
found in sorLA isolated from human brain. Here we show that sorLA, like
sortilin-1/neurotensin receptor-3, whose lumenal domain consists of a
Vps10p domain only, is synthesized as a proreceptor that is cleaved by
furin in late Golgi compartments. We show that the truncation
conditions the Vps10p domain for propeptide inhibitable binding of
neuropeptides and the receptor-associated protein. We further
demonstrate that avid binding of the receptor-associated protein,
apolipoprotein E, and lipoprotein lipase not inhibited by propeptide
occurs to sites located in other lumenal domains. In transfected cells,
about 10% of full-length sorLA were expressed on the cell surface
capable of mediating endocytosis. However, the major pool of receptors
was found in late Golgi compartments, suggesting possible interaction
with newly synthesized ligands. The results show that sorLA, following
activation by truncation, binds multiple ligands and may mediate both
endocytosis and sorting.
Activation and Functional Characterization of the
Mosaic Receptor SorLA/LR11*
,
*
This work was supported by grants from the Danish Medical
Research Council, the Danish Biotechnology Program, the Novo Nordic Foundation, and the Aarhus University Research Foundation.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: Faculty of Biology, Vrije University, de
Boelelaan 1087, 1081 HV Amsterdam, The Netherlands.
§
To whom correspondence should be addressed: Dept. of Medical
Biochemistry, University of Aarhus, Ole Worms Allé, Bldg. 170, DK-8000 Aarhus C, Denmark. Tel.: 45-89-422880; Fax:
45-86-131160; E-mail: jg@biokemi.au.dk.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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