Interaction of Cytosolic Adaptor Proteins with Neuronal Apolipoprotein E Receptors and the Amyloid Precursor Protein*
- From the ‡Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9046 and¶Howard Hughes Medical Institute and Departments of Internal Medicine and Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109
Abstract
Apolipoprotein E, α2-macroglobulin, and amyloid precursor protein (APP) are involved in the development of Alzheimer’s disease. All three proteins are ligands for the low density lipoprotein (LDL) receptor-related protein (LRP), an abundant neuronal surface receptor that has also been genetically linked to Alzheimer’s disease. The cytoplasmic tails of LRP and other members of the LDL receptor gene family contain NPxY motifs that are required for receptor endocytosis. To investigate whether these receptors may have functions that go beyond ligand internalization, e.g. possible roles in cellular signaling, we searched for proteins that might interact with the cytoplasmic tails of the receptors. A family of adaptor proteins containing protein interaction domains that can interact with NPxY motifs has previously been described. Using yeast 2-hybrid and protein coprecipitation approaches in vitro, we show that the neuronal adaptor proteins FE65 and mammalian Disabled bind to the cytoplasmic tails of LRP, LDL receptor, and APP, where they can potentially serve as molecular scaffolds for the assembly of cytosolic multiprotein complexes. FE65 contains two distinct protein interaction domains that interact with LRP and APP, respectively, raising the possibility that LRP can modulate the intracellular trafficking of APP. Tyrosine-phosphorylated mammalian Disabled can recruit nonreceptor tyrosine kinases, such as src and abl, to the cytoplasmic tails of the receptors to which it binds, suggesting a molecular pathway by which receptor/ligand interaction on the cell surface could generate an intracellular signal.
Footnotes
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↵* Supported in part by Grant HL20948 from the National Institutes of Health and by grants from the Keck Foundation and the Perot Family 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.
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↵§ Supported by a Max Kade postdoctoral fellowship.
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↵‖ An investigator of the Howard Hughes Medical Institute.
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↵** An Established Investigator of the American Heart Association and Parke-Davis. To whom correspondence should be addressed, at Dept. of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9046. Tel.: 214-648-5633; Fax: 214-648-8804; E-mail: herz{at}utsw.swmed.edu.
- Abbreviations:
- LRP
-
low density lipoprotein receptor-related protein
- apo
-
apolipoprotein
- APP
-
amyloid precursor protein
- LDL
-
low density lipoprotein
- LDLR
-
LDL receptor
- mDab
-
mammalian disabled
- PID
-
protein interaction domain
- GST
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glutathione S-transferase
- nt
-
nucleotide(s)
- SR-BI
-
scavenger receptor BI.
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- Received August 3, 1998.
- Revision received September 10, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
