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Structure of the human cation-independent mannose 6-phosphate/IGF2 receptor domains 7–11 uncovers the mannose 6-phosphate binding site of domain 9
DOI:
10.1016/j.str.2020.08.002
Authors:
Alice J.
Bochel
(University of Bristol)
,
Christopher
Williams
(University of Bristol; BrisSynBio)
,
Airlie J.
Mccoy
(University of Cambridge)
,
Hans-jürgen
Hoppe
(University of Oxford)
,
Ashley J.
Winter
(University of Bristol)
,
Ryan D.
Nicholls
(University of Bristol)
,
Karl
Harlos
(Wellcome Trust Centre for Human Genetics, University of Oxford)
,
E. Yvonne
Jones
(Wellcome Centre for Human Genetics, University of Oxford)
,
Imre
Berger
(University of Bristol)
,
A. Bassim
Hassan
(University of Oxford)
,
Matthew P.
Crump
(University of Bristol; BrisSynBio)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Structure
State:
Published (Approved)
Published:
September 2020
Diamond Proposal Number(s):
8423
Abstract: The cation-independent mannose 6-phosphate (M6P)/Insulin-like growth factor-2 receptor (CI-MPR/IGF2R) is an ∼300 kDa transmembrane protein responsible for trafficking M6P-tagged lysosomal hydrolases and internalizing IGF2. The extracellular region of the CI-MPR has 15 homologous domains, including M6P-binding domains (D) 3, 5, 9, and 15 and IGF2-binding domain 11. We have focused on solving the first structures of human D7–10 within two multi-domain constructs, D9–10 and D7–11, and provide the first high-resolution description of the high-affinity M6P-binding D9. Moreover, D9 stabilizes a well-defined hub formed by D7–11 whereby two penta-domains intertwine to form a dimeric helical-type coil via an N-glycan bridge on D9. Remarkably the D7–11 structure matches an IGF2-bound state of the receptor, suggesting this may be an intrinsically stable conformation at neutral pH. Interdomain clusters of histidine and proline residues may impart receptor rigidity and play a role in structural transitions at low pH.
Journal Keywords: X-ray crystallography; CI-MPR; IGF2R; P-type lectin; domain 9; mannose 6-phosphate
Subject Areas:
Biology and Bio-materials
Instruments:
B21-High Throughput SAXS
,
I03-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
,
I24-Microfocus Macromolecular Crystallography