A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6

Kaitlyn McGrath, Shivani Agarwal, Marco Tonelli, Mykola Dergai, Anthony L. Gaeta, Andrew K. Shum, Jessica Lacoste, Yongbo Zhang, Wenyu Wen, Daayun Chung, Grant Wiersum, Aishwarya Shevade, Sofia Zaichick, Damian B. van Rossum, Ludmilla Shuvalova, Jeffrey N. Savas, Sergei Kuchin, Mikko Taipale, Kim A. Caldwell, Guy A. CaldwellDirk Fasshauer, Gabriela Caraveo

Research output: Contribution to journalArticlepeer-review

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’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.

Original languageEnglish (US)
Article numbere2016730118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number12
DOIs
StatePublished - Mar 23 2021

All Science Journal Classification (ASJC) codes

  • General

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