Structural assembly of the megadalton-sized receptor for intestinal vitamin B12 uptake and kidney protein reabsorption

Casper Larsen, Anders Etzerodt, Mette Madsen, Karsten Skjødt, Søren Kragh Moestrup, Christian Brix Folsted Andersen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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 B12 (B12) 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 B12 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.

Original languageEnglish
Article number5204
JournalNature Communications
Volume9
Number of pages11
ISSN2041-1723
DOIs
Publication statusPublished - 1. Dec 2018

Keywords

  • Albumins/metabolism
  • Amino Acid Sequence
  • Anemia, Megaloblastic/genetics
  • Animals
  • CHO Cells
  • Cricetulus
  • Crystallography, X-Ray
  • Humans
  • Intestinal Mucosa/metabolism
  • Kidney/metabolism
  • Malabsorption Syndromes/genetics
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Proteins/chemistry
  • Proteinuria/genetics
  • Receptors, Cell Surface/chemistry
  • Sequence Homology, Amino Acid
  • Vitamin B 12 Deficiency/genetics
  • Vitamin B 12/metabolism

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