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J. Cell Sci. 116 (3): 453-461


Research Article

Functional interaction of megalin with the megalinbinding protein (MegBP), a novel tetratrico peptide repeat-containing adaptor molecule

Helle Heibroch Petersen1, Jan Hilpert1, Daniel Militz1, Valerie Zandler1, Christian Jacobsen2, Anton J. M. Roebroek3, and Thomas E. Willnow1,2,*

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 for publication 29 October 2002.

Abstract: 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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