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