期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2016730118
关键词
SNARE; calcineurin; Parkinson's disease; conformation; Ykt6
资金
- NIH [1R15NS104857-01A1]
Ykt6, a soluble SNARE protein, plays a critical role in vesicular fusion pathways. Phosphorylation at a conserved site triggers a conformational change, leading to altered protein interactions and enhanced toxicity in PD models. This study reveals a mechanism regulating Ykt6 conformation and activity with potential implications for Parkinson's disease.
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.
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