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*

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Resumé

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.

OriginalsprogEngelsk
Artikelnummer5204
TidsskriftNature Communications
Vol/bind9
Antal sider11
ISSN2041-1723
DOI
StatusUdgivet - 1. dec. 2018

Fingeraftryk

vitamins
kidneys
Vitamin B 12
helices
assembly
proteins
Kidney
Proteins
Protein Deficiency
Docks
Dimerization
mutations
dimerization
Anchors
albumins
Electron microscopy
Albumins
electron microscopy
Electron Microscopy
Crystal structure

Citer dette

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title = "Structural assembly of the megadalton-sized receptor for intestinal vitamin B12 uptake and kidney protein reabsorption",
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-Gr{\"a}sbeck’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 {\AA} 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.",
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",
author = "Casper Larsen and Anders Etzerodt and Mette Madsen and Karsten Skj{\o}dt and Moestrup, {S{\o}ren Kragh} and Andersen, {Christian Brix Folsted}",
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day = "1",
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Structural assembly of the megadalton-sized receptor for intestinal vitamin B12 uptake and kidney protein reabsorption. / Larsen, Casper; Etzerodt, Anders; Madsen, Mette; Skjødt, Karsten; Moestrup, Søren Kragh; Andersen, Christian Brix Folsted.

I: Nature Communications, Bind 9, 5204, 01.12.2018.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 - 2018/12/1

Y1 - 2018/12/1

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

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

M1 - 5204

ER -