@article{5454313e5f7f4bcfb6e65fcf92f050fe,
title = "A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6",
abstract = "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{\textquoteright}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.",
keywords = "SNARE | calcineurin | Parkinson{\textquoteright}s disease | conformation | Ykt6",
author = "Kaitlyn McGrath and Shivani Agarwal and Marco Tonelli and Mykola Dergai and Gaeta, {Anthony L.} and Shum, {Andrew K.} and Jessica Lacoste and Yongbo Zhang and Wenyu Wen and Daayun Chung and Grant Wiersum and Aishwarya Shevade and Sofia Zaichick and {van Rossum}, {Damian B.} and Ludmilla Shuvalova and Savas, {Jeffrey N.} and Sergei Kuchin and Mikko Taipale and Caldwell, {Kim A.} and Caldwell, {Guy A.} and Dirk Fasshauer and Gabriela Caraveo",
note = "Funding Information: ACKNOWLEDGMENTS. For kindly providing critical reagents, we would like to thank Peter Stirling at the University of British Colombia for providing the Ykt6 yeast temperature-sensitive strain, Congcong He at Northwestern University for providing the CMV-GFP-LC3 stable HeLa cell line, and Andrew Peden at the University of Sheffield for providing the PC4 cell line. Special thanks to Michael Schwake for critical discussions and Robert Vassar for critical reading of the manuscript. This research was partly supported by NIH Grant 1R15NS104857-01A1 to G.A.C. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = mar,
day = "23",
doi = "10.1073/pnas.2016730118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "12",
}