Structure of the Human Cation-Independent Mannose 6-Phosphate/IGF2 Receptor Domains 7-11 Uncovers the Mannose 6-Phosphate Binding Site of Domain 9

Alice J Bochel; Christopher Williams; Airlie J McCoy; Hans-Jürgen Hoppe; Ashley J Winter; Ryan D Nicholls; Karl Harlos; E Yvonne Jones; Imre Berger; A Bassim Hassan; Matthew P Crump

doi:10.1016/j.str.2020.08.002

Structure of the Human Cation-Independent Mannose 6-Phosphate/IGF2 Receptor Domains 7-11 Uncovers the Mannose 6-Phosphate Binding Site of Domain 9

Structure. 2020 Dec 1;28(12):1300-1312.e5. doi: 10.1016/j.str.2020.08.002. Epub 2020 Sep 1.

Authors

Affiliations

¹ School of Chemistry, Cantock's Close, University of Bristol, Bristol BS8 1TS, UK.
² School of Chemistry, Cantock's Close, University of Bristol, Bristol BS8 1TS, UK; BrisSynBio, Life Sciences Building, Tyndall Avenue, Bristol BS8 1TQ, UK.
³ Cambridge Institute for Medical Research, Department of Haematology, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK.
⁴ Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK; dAInomics Ltd, 66 High Street, Bassingbourn Royston SG8 5LF, UK.
⁵ Cancer Research UK Receptor Structure Research Group, Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁶ School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.
⁷ Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. Electronic address: bass.hassan@path.ox.ac.uk.
⁸ School of Chemistry, Cantock's Close, University of Bristol, Bristol BS8 1TS, UK; BrisSynBio, Life Sciences Building, Tyndall Avenue, Bristol BS8 1TQ, UK. Electronic address: matt.crump@bristol.ac.uk.

PMID: 32877646
DOI: 10.1016/j.str.2020.08.002

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.

Keywords: CI-MPR; IGF2R; P-type lectin; X-ray crystallography; domain 9; mannose 6-phosphate.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Humans
Hydrogen-Ion Concentration
Mannosephosphates / chemistry
Mannosephosphates / metabolism
Molecular Docking Simulation
Protein Binding
Protein Multimerization
Receptor, IGF Type 2 / chemistry*
Receptor, IGF Type 2 / metabolism

Substances

IGF2R protein, human
Mannosephosphates
Receptor, IGF Type 2
mannose-6-phosphate

Abstract

Publication types

MeSH terms

Substances

Grants and funding