#late endosome

Protein Sorting and Trafficking

What happens to apotransferrin after iron release in the late endosome?

Transferrin iron delivery exemplifies efficient non-degradative receptor recycling distinct from degradative LDL pathway catabolism. Diferric transferrin ferrotransferrin with two ferric ions plus carbonate binds high specificity transferrin receptor TfR1 homodimer neutral pH surface clustering clathrin AP2 vesicles internalized within minute. Within sorting early endosome acidification around pH 5.5 V-ATPase protonates carbonate coordination Fe3+ released reduced Fe2+ transmembrane metalloreductase STEAP3 then exported cytosol via divalent metal transporter DMT1 SLC11A2 incorporated iron-sulf

Ref: Lodish et al., MCB: Apotransferrin recycling after iron release in late endosome.

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Protein Sorting and Trafficking

The acidic pH in the late endosome causes:

Endosomal maturation involves Rab conversion progressive luminal acidification orchestrated by vacuolar V-type ATPase multisubunit rotary pump hydrolyzing ATP pumping protons generating pH early endosome 6.0-6.5 late 5.5-6.0 lysosome 4.5-5.0. Gradient critical sorting function beyond hydrolysis activation many ligand-receptor complexes exhibit pH dependent affinity due histidine protonation altering charge complementarity. Examples: LDL separates from LDL receptor pH below 6 releasing particle for lysosomal degradation while receptor recycles via retromer, mannose-6-phosphate receptors release

Ref: Maxfield & McGraw, Nat Rev Mol Cell Biol: Endosomal acidification dissociates receptor-ligand complexes.

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Protein Sorting and Trafficking

What would happen if the pH of the late endosome were increased to 6.6?

Dissociation of lysosomal enzymes from mannose-6-phosphate receptors relies on progressive acidification along endocytic pathway driven by V-ATPase multisubunit rotary pump. In trans-Golgi network pH near 6.7 binding between M6P monoester and receptor pocket containing arginine histidine is high affinity nanomolar permitting packaging into vesicles. Upon arrival in late endosomes pH drops via pumping to 5.5-6.0 protonating histidines reducing electrostatic complementarity affinity over hundredfold causing cargo release into lumen while receptors remain membrane bound for retromer VPS26-29-35 r

Ref: Lodish et al., MCB: Acidic late endosome releases M6P enzymes from receptors for lysosome delivery.

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Protein Sorting and Trafficking

Which vesicle coat protein mediates transport from the trans-Golgi to late endosomes?

Sorting at trans-Golgi network directing newly synthesized lysosomal hydrolases and membrane proteins LAMP1 to endosomes uses clathrin coats distinct from plasma membrane but sharing triskelia lattice. Soluble hydrolases bearing mannose-6-phosphate bind M6P receptors whose tails contain tyrosine YXXPhi and acidic dileucine DXXLL motifs recognized by adaptors AP1 gamma-beta1-mu1-sigma1 and monomeric GGAs with VHS domain binding DXXLL. AP1 and GGA recruited by ARF1-GTP and PI4P enriched at TGN cluster clathrin heavy and light triskelia onto TGN membrane forming dense coated buds targeting late e

Ref: Bonifacino & Glick, Cell 2004 Review: Clathrin-coated vesicles from TGN to late endosomes.

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