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Volume 272, Number 42, Issue of October 17, 1997 pp. 26497-26504
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Characterization of an Epithelial ~460-kDa Protein That Facilitates Endocytosis of Intrinsic Factor-Vitamin B₁₂ and Binds Receptor-associated Protein

(Received for publication, April 23, 1997, and in revised form, July 16, 1997)

Henrik Birn , Pierre J. Verroust ^§ , Ebba Nexø ^¶ , Henrik Hager , Christian Jacobsen , Erik I. Christensen and Søren K. Moestrup

From the Departments of  Cell Biology and  Medical Biochemistry, University of Aarhus, and the ^¶ Department of Clinical Biochemistry, Kommunehospitalet, 8000 Aarhus C, Denmark, and ^§ INSERM U64, Hôpital Tenon, 75020 Paris, France

By using receptor-associated protein (RAP) as an affinity target, an intrinsic factor-vitamin B₁₂ (IF-B₁₂)-binding renal epithelial protein of ~460 kDa was copurified together with the transcobalamin-B₁₂-binding 600-kDa receptor, megalin. IF-B₁₂ affinity chromatography of renal cortex membrane from rabbit and man yielded the same ~460-kDa protein. Binding studies including surface plasmon resonance analyses of the protein demonstrated a calcium-dependent and high affinity binding of IF-B₁₂ to a site distinct from the RAP binding site. The high affinity binding of IF-B₁₂ was dependent on complex formation with vitamin B₁₂. Light and electron microscope autoradiography of rat renal cortex cryosections incubated directly with IF-⁵⁷Co-B₁₂ and rat proximal tubules microinjected in vivo with the radioligand demonstrated binding of the ligand to endocytic invaginations of proximal tubule membranes followed by endocytosis and targeting of vitamin B₁₂ to lysosomes. Polyclonal antibodies recognizing the ~460-kDa receptor inhibited the uptake. Immunohistochemistry of kidney and intestine showed colocalization of the IF-B₁₂ receptor and megalin in both tissues. In conclusion, we have identified the epithelial IF-B₁₂-binding receptor as a ~460-kDa RAP-binding protein facilitating endocytosis.

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