Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
Structural assembly of the megadalton-sized receptor for intestinal vitamin B12 uptake and kidney protein reabsorption. / Larsen, Casper; Etzerodt, Anders; Madsen, Mette et al.
In: Nature Communications, Vol. 9, No. 1, 5204, 06.12.2018.Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
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TY - JOUR
T1 - Structural assembly of the megadalton-sized receptor for intestinal vitamin B12 uptake and kidney protein reabsorption
AU - Larsen, Casper
AU - Etzerodt, Anders
AU - Madsen, Mette
AU - Skjødt, Karsten
AU - Moestrup, Søren Kragh
AU - Andersen, Christian Brix Folsted
PY - 2018/12/6
Y1 - 2018/12/6
N2 - 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.
AB - 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.
KW - Albumins/metabolism
KW - Amino Acid Sequence
KW - Anemia, Megaloblastic/genetics
KW - Animals
KW - CHO Cells
KW - Cricetulus
KW - Crystallography, X-Ray
KW - Humans
KW - Intestinal Mucosa/metabolism
KW - Kidney/metabolism
KW - Malabsorption Syndromes/genetics
KW - Mutation
KW - Protein Binding
KW - Protein Conformation
KW - Proteins/chemistry
KW - Proteinuria/genetics
KW - Receptors, Cell Surface/chemistry
KW - Sequence Homology, Amino Acid
KW - Vitamin B 12 Deficiency/genetics
KW - Vitamin B 12/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85058032633&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-07468-4
DO - 10.1038/s41467-018-07468-4
M3 - Journal article
C2 - 30523278
AN - SCOPUS:85058032633
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5204
ER -