Practice question

Soluble acid hydrolases acquire mannose-6-phosphate marker for lysosomal delivery through selective two-step modification restricted to Golgi apparatus, discovered by Kornfeld laboratory. Newly synthesized hydrolases enter ER, receive high-mannose N-glycans, fold with calnexin cycle, then travel to cis-Golgi network. There UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase alpha2 beta2 gamma2 hexamer encoded by GNPTAB and GNPTG recognizes conformational patch on hydrolases and transfers GlcNAc-1-phosphate to C6 hydroxyl of select mannose residues forming phosphodiester intermediate. Enzyme resides in cis-Golgi ensuring early tagging before further trimming. In trans-Golgi network, uncovering enzyme N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase encoded by NAGPA hydrolyzes masking GlcNAc exposing M6P monoester. Only then two P-type lectin receptors 300 kDa cation-independent and 46 kDa cation-dependent bind slightly acidic pH packaging cargo into AP1 and GGA clathrin vesicles to late endosomes where acid releases cargo for lysosomal delivery. Failure cis-phosphorylation causes mucolipidosis II I-cell disease with secreted hydrolases and lysosomal storage phenotype. ER never adds M6P, so phosphorylation definitive marker.