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Passage Many Lysosomal Proteins Are Transported to the Lysosome by the the Cation-Independent

Question 158

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Many lysosomal proteins are transported to the lysosome by the cation-independent mannose 6-phosphate receptor (CI-MPR) .  CI-MPR is a transmembrane protein found in the Golgi apparatus and vesicles.  It contains 15 globular domains folded similarly on the luminal side of the membrane, each of which has up to 3 glycosylation sites and 6−12 cysteine residues that aid in folding.The ability of CI-MPR to recognize multiple different ligands was studied by fluorescent microarray analysis.  Microarray analysis was performed by cross-linking candidate ligands such as plasminogen, insulin-like growth factor 2 (IGF-II) , and mannose 6-phosphate (M6P) , to glass slides.  The slides were then incubated with full-length CI-MPR or recombinantly expressed CI-MPR domains, followed by incubation with an anti−CI-MPR antibody.  A fluorescently labeled antibody that binds the first antibody was then added, and the relative fluorescence levels of each candidate ligand were compared.  Higher fluorescence levels correspond to greater binding.Experiment 1Microarray analysis was carried out on slides containing varying levels of candidate ligands, and binding affinities of each CI-MPR domain for its primary ligand were estimated.  Table 1 shows the results.Experiment 2Domains 3, 5, and 9 bind carbohydrates.  Amino acids in these domains were mutated to determine which are required for binding.  Based on this experiment, scientists concluded that Arg, Glu, and Tyr are required for carbohydrate binding by domains 3, 5, and 9 of CI-MPR.Table 1
Passage Many lysosomal proteins are transported to the lysosome by the cation-independent mannose 6-phosphate receptor (CI-MPR) .  CI-MPR is a transmembrane protein found in the Golgi apparatus and vesicles.  It contains 15 globular domains folded similarly on the luminal side of the membrane, each of which has up to 3 glycosylation sites and 6−12 cysteine residues that aid in folding.The ability of CI-MPR to recognize multiple different ligands was studied by fluorescent microarray analysis.  Microarray analysis was performed by cross-linking candidate ligands such as plasminogen, insulin-like growth factor 2 (IGF-II) , and mannose 6-phosphate (M6P) , to glass slides.  The slides were then incubated with full-length CI-MPR or recombinantly expressed CI-MPR domains, followed by incubation with an anti−CI-MPR antibody.  A fluorescently labeled antibody that binds the first antibody was then added, and the relative fluorescence levels of each candidate ligand were compared.  Higher fluorescence levels correspond to greater binding.Experiment 1Microarray analysis was carried out on slides containing varying levels of candidate ligands, and binding affinities of each CI-MPR domain for its primary ligand were estimated.  Table 1 shows the results.Experiment 2Domains 3, 5, and 9 bind carbohydrates.  Amino acids in these domains were mutated to determine which are required for binding.  Based on this experiment, scientists concluded that Arg, Glu, and Tyr are required for carbohydrate binding by domains 3, 5, and 9 of CI-MPR.Table 1 Adapted from Bohnsack RN, Song X, Olson LJ, et al. Cation-independent mannose 6-phosphate receptor: a composite of distinct phosphomannosyl binding sites. J Biol Chem. 2009;284(50) :35215-26. -Residues in the binding pockets of domains 3, 5, and 9 interact with carbohydrates through hydrogen bonds.  In Experiment 2, tyrosine residues were mutated to remove hydrogen bonding while minimizing changes in the shape of the active site.  Tyrosine residues were most likely mutated to: A) Thr B) Phe C) Ala D) His Adapted from Bohnsack RN, Song X, Olson LJ, et al. Cation-independent mannose 6-phosphate receptor: a composite of distinct phosphomannosyl binding sites. J Biol Chem. 2009;284(50) :35215-26.
-Residues in the binding pockets of domains 3, 5, and 9 interact with carbohydrates through hydrogen bonds.  In Experiment 2, tyrosine residues were mutated to remove hydrogen bonding while minimizing changes in the shape of the active site.  Tyrosine residues were most likely mutated to:


A) Thr
B) Phe
C) Ala
D) His

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