46-kDa Mannose 6-phosphate-Specific Receptor: Biosynthesis, Processing, Subcellular Location and Topology

Stein, Martin; Braulke, Thomas; Krentler, C; Hasilík, Andrej; Figura, Kurt Von

doi:10.1515/bchm3.1987.368.2.937

Cited by 81 publications

(59 citation statements)

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“…Perdue et al (33) have reported that the M6P/IGF-II receptor is a monomer when solubilized, whereas Stein et al (34) suggested that it may exist as a dimer in the plasma membrane, as determined by cross-linking studies. The M6P/ IGF-II receptor was solubilized and purified from fresh bovine liver.…”

Section: Intermolecular Cross-linking Of M6p/igf-ii Receptors Is Respmentioning

confidence: 99%

The Rate of Internalization of the Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor Is Enhanced by Multivalent Ligand Binding

York

Arneson

Gregory

et al. 1999

Journal of Biological Chemistry

105

117

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The cation-independent mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF-II receptor) undergoes constitutive endocytosis, mediating the internalization of two unrelated classes of ligands, mannose 6-phosphate (Man-6-P)-containing acid hydrolases and insulin-like growth factor II (IGF-II). To determine the role of ligand valency in M6P/IGF-II receptor-mediated endocytosis, we measured the internalization rates of two ligands, ␤-glucuronidase (a homotetramer bearing multiple Man-6-P moieties) and IGF-II. We found that ␤-glucuronidase entered the cell ϳ3-4-fold faster than IGF-II. Unlabeled ␤-glucuronidase stimulated the rate of internalization of 125 I-IGF-II to equal that of 125 I-␤-glucuronidase, but a bivalent synthetic tripeptide capable of occupying both Man-6-P-binding sites on the M6P/IGF-II receptor simultaneously did not. A mutant receptor with one of the two Man-6-P-binding sites inactivated retained the ability to internalize ␤-glucuronidase faster than IGF-II. Thus, the increased rate of internalization required a multivalent ligand and a single Man-6-P-binding site on the receptor. M6P/IGF-II receptor solubilized and purified in Triton X-100 was present as a monomer, but association with ␤-glucuronidase generated a complex composed of two receptors and one ␤-glucuronidase. Neither IGF-II nor the synthetic peptide induced receptor dimerization. These results indicate that intermolecular cross-linking of the M6P/IGF-II receptor occurs upon binding of a multivalent ligand, resulting in an increased rate of internalization.The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF-II receptor) 1 is a type I transmembrane glycoprotein that cycles through the Golgi, endosomes, and the plasma membrane to carry out its role in the biogenesis of lysosomes and in the clearance of the polypeptide insulin-like growth factor II (IGF-II) (1, 2). In the Golgi, the receptor binds newly synthesized acid hydrolases modified with mannose 6-phosphate (Man-6-P) residues on their asparagine-linked oligosaccharides and transports them to endosomes via clathrincoated vesicles (3-5). The acid hydrolases are released in the acidified endosome and then packaged into lysosomes while the receptor either returns to the Golgi to bind another ligand or moves to the plasma membrane (6, 7). At the plasma membrane, the M6P/IGF-II receptor mediates internalization of Man-6-P-containing ligands and IGF-II (3,5,8).The interactions of IGF-II and Man-6-P-containing ligands with the M6P/IGF-II receptor have been characterized in several studies (8 -12). The extracellular portion of the M6P/ IGF-II receptor contains 15 homologous repeating domains of ϳ147 amino acids each (13). Domains 3 and 9 (numbering from the amino terminus) each bind 1 mol of Man-6-P, and the single IGF-II-binding site has been mapped to domain 11 in the extracellular region (14 -16). Man-6-P residues do not inhibit binding of IGF-II to the receptor, verifying that the two ligandbinding sites are distinct. However, proteins containing Man-6...

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Section: Intermolecular Cross-linking Of M6p/igf-ii Receptors Is Respmentioning

confidence: 99%

The Rate of Internalization of the Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor Is Enhanced by Multivalent Ligand Binding

York

Arneson

Gregory

et al. 1999

Journal of Biological Chemistry

105

117

View full text Add to dashboard Cite

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“…Characterization of purified forms of the receptor by gel filtration and sucrose density gradient centrifugation has suggested that the receptor exists in solution in a monomeric form (17,18), whereas chemical cross-linking studies have demonstrated that the receptor forms aggregates in the membranes of intact cells (19). Recent observations, however, suggest that the IGF2R may bind multivalent Man-6-P-bearing lysosomal enzymes by forming an oligomeric receptor complex.…”

mentioning

confidence: 99%

Dimerization of the Insulin-like Growth Factor II/Mannose 6-Phosphate Receptor

Byrd¹,

Park²,

Schaffer³

et al. 2000

Journal of Biological Chemistry

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The insulin-like growth factor II/mannose 6-phosphate receptor (IGF2R) interacts with lysosomal enzymes through two binding domains in its extracytoplasmic domain. We report in the accompanying article (Byrd, J. C., and MacDonald, R. G. (2000) J. Biol. Chem. 275, 18638 -18646) that only one of the two extracytoplasmic mannose 6-phosphate (Man-6-P) binding domains is necessary for high affinity Man-6-P ligand binding, suggesting that, like the cation-dependent Man-6-P receptor, oligomerization of the IGF2R contributes to high affinity interaction with lysosomal enzymes. In the present study, we have directly characterized both naturally occurring and engineered forms of the IGF2R for their ability to form oligomeric structures. Whereas gel filtration chromatography suggested that purified bovine IGF2R species exist in a monomeric form, native gel electrophoresis allowed for the separation of dimeric and monomeric forms of the receptors with distinct phosphomannosyl ligand binding characteristics. The ability of the IGF2R to form oligomeric complexes was confirmed and localized to the extracytoplasmic domain through the use of epitope-tagged soluble IGF2R constructs bearing deletions of the transmembrane and cytoplasmic domains. Finally, chimeric receptors were engineered containing the extracytoplasmic and transmembrane domains of the IGF2R fused to the cytoplasmic domain of the epidermal growth factor receptor with which dimerization of the chimeras could be monitored by measuring autophosphorylation. Collectively, these results show that the IGF2R is capable of forming oligomeric complexes, most likely dimers, in the absence of Man-6-P ligands.

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“…Immunoprecipitated mCTSD was treated with 10 m-units of peptide N-glycosidase F (Roche Molecular Biochemicals, Mannheim, Germany) for 20 h at 37 mC [35].…”

Section: Other Methodsmentioning

confidence: 99%

A replacement of the active-site aspartic acid residue 293 in mouse cathepsin D affects its intracellular stability, processing and transport in HEK-293 cells

Partanen

Storch²,

Löffler

et al. 2003

Biochemical Journal

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The substitution of an active-site aspartic acid residue by asparagine in the lysosomal protease cathepsin D (CTSD) results in a loss of enzyme activity and severe cerebrocortical atrophy in a novel form of neuronal ceroid lipofuscinosis in sheep [Tyynela$ , Sohar, Sleat, Gin, Donnelly, Baumann, Haltia and Lobel (2000) EMBO J. 19, [2786][2787][2788][2789][2790][2791][2792]. In the present study we have introduced the corresponding mutation by replacing aspartic acid residue 293 with asparagine (D293N) into the mouse CTSD cDNA to analyse its effect on synthesis, transport and stability in transfected HEK-293 cells. The complete inactivation of mutant D293N mouse CTSD was confirmed by a newly developed fluorimetric quantification system. Moreover, in the heterologous overexpression systems used, mutant D293N mouse

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46-kDa Mannose 6-phosphate-Specific Receptor: Biosynthesis, Processing, Subcellular Location and Topology

Cited by 81 publications

References 1 publication

The Rate of Internalization of the Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor Is Enhanced by Multivalent Ligand Binding

The Rate of Internalization of the Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor Is Enhanced by Multivalent Ligand Binding

Dimerization of the Insulin-like Growth Factor II/Mannose 6-Phosphate Receptor

A replacement of the active-site aspartic acid residue 293 in mouse cathepsin D affects its intracellular stability, processing and transport in HEK-293 cells

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