Functional interaction of megalin with the megalinbinding protein (MegBP), a novel tetratrico peptide repeat-containing adaptor molecule.
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.
Petersen
Helle Heibroch
HH
Max-Delbrueck-Center for Molecular Medicine and Medical Faculty of the Free University of Berlin, Germany.
Hilpert
Jan
J
Militz
Daniel
D
Zandler
Valerie
V
Jacobsen
Christian
C
Roebroek
Anton J M
AJ
Willnow
Thomas E
TE
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000302:isolation & purification*; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D001665:Binding Sites / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D004705:Endocytosis / Q000502:physiology*; D005057:Eukaryotic Cells / Q000378:metabolism*; D005809:Genes, Regulator / Q000502:physiology*; D006801:Humans; D008024:Ligands; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000302:isolation & purification*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D018076:DNA, Complementary; C476844:LRP2BP protein, human; D008024:Ligands; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D034521:Nuclear Matrix-Associated Proteins; D010455:Peptides; C466999:SPHKAP protein, human; C476831:megalinbinding protein, mouse