The propeptide of Aminopeptidase 1 mediates aggregation and vesicle formation in the Cytoplasm-to-vacuole targeting pathway.

Misfolded protein aggregation causes disease and ageing; autophagy counteracts this by eliminating damaged components, enabling cells to survive starvation. The Cytoplasm-to-vacuole-targeting (Cvt) pathway in yeast encompasses the aggregation of the premature form of Aminopeptidase 1 (prApe1) in cytosol, and its sequestration by autophagic proteins into a vesicle for vacuolar transport. ...
We show that the propeptide of Ape1 is important for aggregation and vesicle formation, it is sufficient for binding to prApe1 and Atg19. Defective aggregation disrupts vacuolar transport, suggesting aggregate shape is important in vesicle formation, while Atg19 binding is not sufficient for vacuolar transport. Aggregation involves hydrophobicity, while Atg19 binding requires additional electrostatic interactions. Ape1 dodecamerization may cluster propeptides into trimeric structures, with sufficient affinity to form propeptide hexamers by binding to other dodecamers, causing aggregation. We show that Ape1 aggregates bind Atg19 and Atg8 in vitro, this could be used as a scaffold for an in vitro assay of autophagosome formation to elucidate the mechanisms of autophagy.
J. Biol. Chem.
Date: Nov. 28, 2011
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