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First published online 4 December 2002
doi: 10.1242/jcs.00243
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Research Article |
1 Max-Delbrueck-Center for Molecular Medicine and 2Medical Faculty of
the Free University of Berlin, Germany
2 Department of Medical Biochemistry, University of Aarhus, Aarhus,
Denmark
3 Center for Human Genetics, K. U. Leuven and Flanders Interuniversity Institute
for Biotechnology, Leuven, Belgium
* Author for correspondence (e-mail: willnow{at}mdc-berlin.de)
Accepted 29 October 2002
Megalin is a member of the LDL receptor gene family that plays an important role in forebrain development and in cellular vitamin D metabolism through endocytic uptake of vitamin D metabolites. Similar to other receptors in this gene family, megalin is believed to functionally interact with intracellular proteins through adaptors that bind to the receptor tail and regulate its endocytic and signal transducing activities. Using yeast two-hybrid screens, we identified a novel scaffold protein with tetratrico peptide repeats, the megalin-binding protein (MegBP) that associates with the receptor. The binding site of MegBP was mapped to an N-terminal region on the receptor tail harboring a proline-rich peptide element. MegBP binding did not block the endocytic activity of the receptor; however, overexpression resulted in cellular lethality. In further screens, we identified proteins that bound to MegBP and thus might be recruited to the megalin tail. MegBP-interacting partners included several transcriptional regulators such as the SKI-interacting protein (SKIP), a co-activator of the vitamin D receptor. These finding suggest a model whereby megalin directly participates in transcriptional regulation through controlled sequestration or release of transcription factors via MegBP.
Key words: Scaffold protein, Endocytosis, Forebrain development, LDL receptor gene family, Vitamin D metabolism
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