Ligand interactions of the cation-independent mannose 6-phosphate receptor

Tong, Peter C.Y.; Gregory, Walter; Kornfeld, Stuart

doi:10.1016/s0021-9258(18)83136-2

Cited by 178 publications

(36 citation statements)

References 41 publications

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“…In addition, cation-dependent M6P receptor does not bind M6P at neutral pH, suggesting physiologic pH7.4 only allows CI-M6P receptors to be responsible for P-GUS uptake. 35,36 Currently, the mechanisms of action for brain uptake of [ 131 I]P-GUS by insulin and LPS remain speculative. The insulin receptor belongs to the receptor tyrosine kinase family which has endothelial nitric oxide synthase (NOS) as its downstream signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic manipulation of lysosomal enzyme transport across the blood–brain barrier

Urayama¹,

Grubb

Sly

et al. 2015

J Cereb Blood Flow Metab

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The adult blood-brain barrier, unlike the neonatal blood-brain barrier, does not transport lysosomal enzymes into brain, making enzyme replacement therapy ineffective in treating the central nervous system symptoms of lysosomal storage diseases. However, enzyme transport can be re-induced with alpha-adrenergics. Here, we examined agents that are known to alter the blood-brain barrier transport of large molecules or to induce lysosomal enzyme transport across the blood-brain barrier ((AE)epinephrine, insulin, retinoic acid, and lipopolysaccharide) in 2-week-old and adult mice. In 2-week-old adolescent mice, all these pharmacologic agents increased brain and heart uptake of phosphorylated human b-glucuronidase. In 8-week-old adult mice, manipulations with (AE)epinephrine, insulin, and retinoic acid were significantly effective on uptake by brain and heart. The increased uptake of phosphorylated human b-glucuronidase was inhibited by mannose 6-phosphate for the agents (AE)epinephrine and retinoic acid and by L-NG-nitroarginine methyl ester for the agent lipopolysaccharide in neonatal and adult mice. An in situ brain perfusion study revealed that retinoic acid directly modulated the transport of phosphorylated human b-glucuronidase across the blood-brain barrier. The present study indicates that there are multiple opportunities to at least transiently induce phosphorylated human b-glucuronidase transport at the adult blood-brain barrier.

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Section: Discussionmentioning

confidence: 99%

Pharmacologic manipulation of lysosomal enzyme transport across the blood–brain barrier

Urayama¹,

Grubb

Sly

et al. 2015

J Cereb Blood Flow Metab

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“…There have also been multiple reports that bi-phosphorylated oligosaccharides exhibit higher affinity binding to the CI-MPR than mono-phosphorylated ligands (Distler et al, 1991;Tong et al, 1989) and a dynamic state of CI-MPR that brings the M6P mono-ester sites of domain 3 and 9 to within 45-85 Å has been proposed (Olson et al, 2004b). The distance between domain 3 and of the same chain in our model is ~58 Å. Conversely our dimeric model separates the M6P binding sites of the two domain 9s by a distance of ~22 Å which might be compatible with binding ligands bearing more than one M6P glycan (Fei et al, 2008).…”

Section: Model For Human Ci-mpr Extracellular Regionmentioning

confidence: 99%

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

et al. 2020

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The cation-independent mannose 6-phosphate (M6P)/ Insulin-like growth factor-2 receptor (CI-MPR/ IGF2R) is a ~300 kDa transmembrane protein responsible for trafficking M6P-tagged lysosomal hydrolases and the internalisation of IGF2. Insulin-like growth factor 2 (IGF2). The extracellular region of the CI-MPR is composed of 15 has fifteen homologous domains including M6P binding domains (D) D3, D5, D9 and D15 and IGF2 binding D11. but how it interacts with extracellular ligands at neutral pH is poorly understood. We have focused structural work on key CI-MPR domains of human CI-MPR and report the first structures of human D7, D8, D9 and D10 within two multi-domain constructs, D9-10 and D7-11. Together These structures provide the first high-resolution description of the high-affinity M6P binding domain D9. Domain 9 stabilises a well-defined hub formed by D7-11 in which whereby two penta-domains intertwine to form a dimeric helical-type coil. Remarkably the D7-11 ligand free structure of this penta-domain closely matches the IGF2 bound state suggesting this may be an intrinsically stable conformation at neutral pH. An Interdomain clusters of histidine and proline residues identified between several pairs of domains impart rigidity and may impart receptor rigidity and play a role in structural transitions of the receptor at low pH.

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“…However, the current U.S. Food and Drug Administration approved rhGAA ERT has a low abundance of M6P, particularly bisphosphorylated high-mannose N-glycans (bearing two M6Ps on same N-glycan), which severely limits cellular uptake of ERT at low interstitial enzyme concentrations. Bisphosphorylated N-glycans are known to have the highest binding affinity of all known carbohydrate structures for the CI-MPR and enable binding at low nanomolar concentrations ( 12 , 14 ). Approximately only 1% of N-glycans on the standard-of-care rhGAA ERT bear bis -M6P ( 13 , 15 ).…”

mentioning

confidence: 99%

“…Approximately only 1% of N-glycans on the standard-of-care rhGAA ERT bear bis -M6P ( 13 , 15 ). This ERT contains predominantly monophosphorylated glycans that are known to have approximately 3000-fold lower affinity for CI-MPR than bisphosphorylated N-glycans ( 14 , 15 ). Because monophosphorylated N-glycans cannot bind the CI-MPR at low nanomolar enzyme concentrations, this leads to inefficient cellular uptake and lysosomal delivery ( 14 ).…”

mentioning

confidence: 99%

“…This ERT contains predominantly monophosphorylated glycans that are known to have approximately 3000-fold lower affinity for CI-MPR than bisphosphorylated N-glycans ( 14 , 15 ). Because monophosphorylated N-glycans cannot bind the CI-MPR at low nanomolar enzyme concentrations, this leads to inefficient cellular uptake and lysosomal delivery ( 14 ). Cells from patients with Pompe disease also have defects in CI-MPR trafficking and surface expression ( 16 ), compounding these difficulties in target muscle cells, where pathology is often widespread at the time of treatment.…”

mentioning

confidence: 99%

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Endolysosomal N-glycan processing is critical to attain the most active form of the enzyme acid alpha-glucosidase

Selvan

Mehta

Venkateswaran

et al. 2021

Journal of Biological Chemistry

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Acid alpha-glucosidase (GAA) is a lysosomal glycogen-catabolizing enzyme, the deficiency of which leads to Pompe disease. Pompe disease can be treated with systemic recombinant human GAA (rhGAA) enzyme replacement therapy (ERT), but the current standard of care exhibits poor uptake in skeletal muscles, limiting its clinical efficacy. Furthermore, it is unclear how the specific cellular processing steps of GAA after delivery to lysosomes impact its efficacy. GAA undergoes both proteolytic cleavage and glycan trimming within the endolysosomal pathway, yielding an enzyme that is more efficient in hydrolyzing its natural substrate, glycogen. Here, we developed a tool kit of modified rhGAAs that allowed us to dissect the individual contributions of glycan trimming and proteolysis on maturation-associated increases in glycogen hydrolysis using in vitro and in cellulo enzyme processing, glycopeptide analysis by MS, and high-pH anion-exchange chromatography with pulsed amperometric detection for enzyme kinetics. Chemical modifications of terminal sialic acids on N-glycans blocked sialidase activity in vitro and in cellulo , thereby preventing downstream glycan trimming without affecting proteolysis. This sialidase-resistant rhGAA displayed only partial activation after endolysosomal processing, as evidenced by reduced catalytic efficiency. We also generated enzymatically deglycosylated rhGAA that was shown to be partially activated despite not undergoing proteolytic processing. Taken together, these data suggest that an optimal rhGAA ERT would require both N-glycan and proteolytic processing to attain the most efficient enzyme for glycogen hydrolysis and treatment of Pompe disease. Future studies should examine the amenability of next-generation ERTs to both types of cellular processing.

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Ligand interactions of the cation-independent mannose 6-phosphate receptor

Cited by 178 publications

References 41 publications

Pharmacologic manipulation of lysosomal enzyme transport across the blood–brain barrier

Pharmacologic manipulation of lysosomal enzyme transport across the blood–brain barrier

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

Endolysosomal N-glycan processing is critical to attain the most active form of the enzyme acid alpha-glucosidase

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