Structural assembly of the megadalton-sized receptor for intestinal vitamin B<sub>12</sub> uptake and kidney protein reabsorption.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30523278.
- Also identified by DOI 10.1038/s41467-018-07468-4 and PMC identifier 6283879.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The endocytic receptor cubam formed by the 460-kDa protein cubilin and the 45-kDa transmembrane protein amnionless (AMN), is essential for intestinal vitamin B<sub>12</sub> (B<sub>12</sub>) uptake and for protein (e.g. albumin) reabsorption from the kidney filtrate. Loss of function of any of the two components ultimately leads to serious B<sub>12</sub> deficiency and urinary protein loss in humans (Imerslund-Gräsbeck's syndrome, IGS). Here, we present the crystal structure of AMN in complex with the amino-terminal region of cubilin, revealing a sophisticated assembly of three cubilin subunits combining into a single intertwined β-helix domain that docks to a corresponding three-faced β-helix domain in AMN. This β-helix-β-helix association thereby anchors three ligand-binding cubilin subunits to the transmembrane AMN. Electron microscopy of full-length cubam reveals a 700-800 Å long tree-like structure with the potential of dimerization into an even larger complex. Furthermore, effects of known human mutations causing IGS are explained by the structural information.
Medical subject headings
- Albumins
- Intestinal Mucosa
- Kidney
- Proteins
- Receptors, Cell Surface
- Vitamin B 12