A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6.
Ykt6 is a soluble N-ethylmaleimide sensitive factor activating protein receptor (SNARE) critically involved in diverse vesicular fusion pathways. While most SNAREs rely on transmembrane domains for their activity, Ykt6 dynamically cycles between the cytosol and membrane-bound compartments where it is active. The mechanism that regulates these transitions and allows Ykt6 to achieve specificity toward vesicular pathways is unknown. Using a Parkinson's disease (PD) model, we found that Ykt6 is phosphorylated at an evolutionarily conserved site which is regulated by Ca2+ signaling. Through a multidisciplinary approach, we show that phosphorylation triggers a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. In the phosphorylated open form, the spectrum of protein interactions changes, leading to defects in both the secretory and autophagy pathways, enhancing toxicity in PD models. Our studies reveal a mechanism by which Ykt6 conformation and activity are regulated with potential implications for PD.
['McGrath|Kaitlyn|K|0000-0002-3151-0439', 'Agarwal|Shivani|S|', 'Tonelli|Marco|M|0000-0002-7700-5745', 'Dergai|Mykola|M|', 'Gaeta|Anthony L|AL|0000-0003-2959-7990', 'Shum|Andrew K|AK|', 'Lacoste|Jessica|J|', 'Zhang|Yongbo|Y|0000-0002-8216-1371', 'Wen|Wenyu|W|0000-0002-0798-4730', 'Chung|Daayun|D|', 'Wiersum|Grant|G|', 'Shevade|Aishwarya|A|', 'Zaichick|Sofia|S|', 'van Rossum|Damian B|DB|', 'Shuvalova|Ludmilla|L|0000-0003-1702-6998', 'Savas|Jeffrey N|JN|0000-0002-8173-5580', 'Kuchin|Sergei|S|0000-0002-1621-8456', 'Taipale|Mikko|M|', 'Caldwell|Kim A|KA|0000-0003-1580-6122', 'Caldwell|Guy A|GA|0000-0002-8283-9090', 'Fasshauer|Dirk|D|0000-0002-1040-4282', 'Caraveo|Gabriela|G|']
D000596:Amino Acids D001343:Autophagy D002352:Carrier Proteins D002462:Cell Membrane D017124:Conserved Sequence D019143:Evolution, Molecular D008958:Models, Molecular D010766:Phosphorylation D011485:Protein Binding D011487:Protein Conformation D054730:Protein Interaction Domains and Motifs D050683:R-SNARE Proteins D013329:Structure-Activity Relationship
conformation SNARE Ykt6 Parkinson’s disease calcineurin