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Structure of the LDL Receptor Extracellular Domain at Endosomal pH
Gabby Rudenko,1Lisa Henry,13Keith Henderson,4Konstantin Ichtchenko,2*Michael S. Brown,2Joseph L. Goldstein,2Johann Deisenhofer13
The low-density lipoprotein receptor mediates cholesterol
homeostasis through endocytosis of lipoproteins. It discharges itsligand in the endosome at pH < 6. In the crystal structure atpH = 5.3, the ligand-binding domain (modules R2 to R7) folds backas an arc over the epidermal growth factor precursor homologydomain
(the modules A, B, propeller, and C). The modules R4and R5, which
are critical for lipoprotein binding, associatewith the propeller
via their calcium-binding loop. We proposea mechanism for lipoprotein
release in the endosome whereby the propeller functions as an
alternate substrate for the ligand-bindingdomain, binding in a
calcium-dependent way and promoting lipoproteinrelease.
1 Department of Biochemistry,
2 Department of Molecular Genetics, University of
Texas Southwestern Medical Center, 5323 Harry Hines Boulevard Y4-206,
Dallas, TX 75390, USA.
3 Howard Hughes
Medical Institute,
4 Berkeley Center for
Structural Biology, Lawrence Berkeley Laboratory, MS 6R2100,
1 Cyclotron Road, Berkeley, CA 94720, USA.
*
Present address: New York University School of Medicine,
550 First Avenue, New York, NY 10016, USA.
To whom correspondence should be addressed. E-mail:
Johann.Deisenhofer{at}UTSouthwestern.edu
The editors suggest the following Related Resources on Science sites:
In Science Magazine
PERSPECTIVES
Thomas L. Innerarity (20 December 2002) Science298 (5602), 2337.
[DOI: 10.1126/science.1080669] |Summary »|Full Text »|PDF »
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propeller, and C). The modules R4 and R5, which
are critical for lipoprotein binding, associate with the 
