| Structural highlights
Function
[MPRI_HUMAN] Transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelyosomal compartment where the low pH mediates the dissociation of the complex. This receptor also binds IGF2. Acts as a positive regulator of T-cell coactivation, by binding DPP4.[1]
Publication Abstract from PubMed
The cation-independent mannose 6-phosphate (M6P)/Insulin-like growth factor-2 receptor (CI-MPR/IGF2R) is an approximately 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.
Structure of the Human Cation-Independent Mannose 6-Phosphate/IGF2 Receptor Domains 7-11 Uncovers the Mannose 6-Phosphate Binding Site of Domain 9.,Bochel AJ, Williams C, McCoy AJ, Hoppe HJ, Winter AJ, Nicholls RD, Harlos K, Jones EY, Berger I, Hassan AB, Crump MP Structure. 2020 Sep 1. pii: S0969-2126(20)30284-7. doi:, 10.1016/j.str.2020.08.002. PMID:32877646[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ikushima H, Munakata Y, Ishii T, Iwata S, Terashima M, Tanaka H, Schlossman SF, Morimoto C. Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8439-44. PMID:10900005
- ↑ Bochel AJ, Williams C, McCoy AJ, Hoppe HJ, Winter AJ, Nicholls RD, Harlos K, Jones EY, Berger I, Hassan AB, Crump MP. 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 Sep 1. pii: S0969-2126(20)30284-7. doi:, 10.1016/j.str.2020.08.002. PMID:32877646 doi:http://dx.doi.org/10.1016/j.str.2020.08.002
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