Abstract
The small GTP-binding protein Rab12 plays an important role in the initiation of starvation-induced macroautophagy (autophagy) and is activated by the guanine-nucleotide exchange factor DENND3. However, the molecular mechanism by which DENND3 becomes activated has remained elusive. Xu and McPherson now identify a novel mechanism of DENND3 intramolecular binding that is regulated by the phosphorylation of a single tyrosine residue.
Highlights
Autophagy is a means of selectively marking cellular organelles for lysosomal degradation and plays a vital role in the recycling of proteins during stress caused by nutrient deprivation (1)
Because the “linker” region of DENND3 contains both serines 554 and 572 that are phosphorylated by Unc-51-like kinase (ULK), the authors initially hypothesized that the linker region might interact with the DENN domain and inhibit guanine nucleotide exchange factor (GEF) activity and that ULK phosphorylation might release this auto-inhibition
Using a series of very exacting pulldown experiments, they demonstrated that binding does occur; surprisingly, the binding was mediated by amino acids 935– 973 of the linker, far removed from the serines that are phosphorylated by ULK
Summary
Autophagy is a means of selectively marking cellular organelles for lysosomal degradation and plays a vital role in the recycling of proteins during stress caused by nutrient deprivation (1). In this exciting paper by Xu and McPherson (6), the authors shed new light on the mechanism by which the Rab[12] GEF, DENND3, becomes activated upon serum starvation.
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