The intrinsic factor-vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins: Keys to renal toxicity, hypertension and Imerslund-

6^th Annual conference on Clinical & Pediatric Nephrology

May 09-10, 2016 New Orleans, USA

Timothy Hammond

Durham VAMC, USA
Duke University School of Medicine, USA

Posters & Accepted Abstracts: J Nephrol Ther

Abstract :

The present report shows the molecular characterization of the rat 460 kDa epithelial glycoprotein that functions as the receptor facilitating uptake of intrinsic factor vitamin B12 complexes in the intestine and kidney. The same receptor represents also the yolk sac target for teratogenic antibodies causing fetal malformations in rats. Determination of its primary structure by cDNA cloning identified a novel type of peripheral membrane receptor characterized by a cluster of eight epidermal growth factor type domains followed by a cluster of 27 CUB domains. In accordance with the absence of a hydrophobic segment, the receptor could be released from renal cortex membranes by non-enzymatic and non-solubilizing procedures. The primary structure has no similarity to known endocytic receptors but displays homology to epidermal growth factor and CUB domain proteins involved in fetal development, e.g. the bone morphogenic proteins. Electron microscopic immune-gold double labeling of rat yolk sac and renal proximal tubules demonstrated sub-cellular co-localization with the endocytic receptor megalin, which is expressed in the same epithelia as the 460 kDa receptor. Furthermore, megalin affinity chromatography and surface Plasmon resonance analysis revealed a calcium dependent high affinity binding of the 460 kDa receptor to megalin, which thereby may mediate its vesicular trafficking. Due to the high number of CUB domains, accounting for 88% of the protein mass, we propose the name cubilin for the novel receptor. Ligands include renal toxins such as gentamicin and heavy metal carrying metallothioneins, angiotensin 1-1 and 1-8. Genetic defects in cubilin are the basis for Imerslund-Grasbeck syndrome.

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