Targeting to Lysosomes
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Lysosomes distinct properties
Stomach of the cell -Part of HP -Acidic at pH 5 because of a proton pump
2 Vesicular trafficking pathways
• (Entering) Endocytosis AP-2 and clathrin • (Leaving) TGN to endosomes GGA and clathrin
Endosomes
Point of convergence of for endocytic and biosynthetic pathway
Mannose-6-Phosphate
Sorts lysosomes
Main signal for sorting to lysosome, recognized by, and how are they generated
M6P modification is recognized by M6P receptor (MPR). Mannosylated precursor have phospho-GlcNAc added during cis-Golgi and uncovered at TGN
I-cell patients lack what how is this resolved
They lack GlcNAc phosphotransferase resulting for their lysosome enzymes to be secreted. They add exogenous M6P-modified lysosomal enyzmes. They found that 10% of CI-MPR are in the cell surface to salvage secreted lysosomal enzymes.
GlcNAc phosphotransferase
Adds GlcNAc-P to lysosomal enzymes, Recognizes UDP-GlcNAc and signal patch of lysosomal enzyme
Signal patch sufficient?
they used cathepsin D and a secreted protein, pepsinogen that is not phosphorylate and made a hybrid of the signal patch. pepsinogen had a similar 3D structure as CatD and was phosphorylated.
MPR and how do they release their cargo
MPR bind M6P packaged in tor clathrin-coated vesicles delivered to early endosomes. They release their cargo because of the drop in pH at endosome. MPR are recycled back to TGN
2 types of MPR
CI-MPR (300kda) CD-MPR (46kDa)
2 experiments that found CI-MPR to be at the cell surface
• They inhibited CI-MPR and found lysosomal enzymes to be secreted