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 Shum, Jessica Lacoste, Yongbo Zhang, Wenyu Wen, Daayun Chung, G. Wiersum, Aishwarya Shevade, Sofia Zaichick, Damian B. van Rossum, L. Shuvalova, Jeffrey N. Savas, Sergei Kuchin, Mikko Taipale, Kim A. Caldwell, Guy A. Caldwell, Dirk Fasshauer, Gabriela Caraveo
Abstract
Significance Ykt6 is a conserved SNARE that plays critical roles along multiple vesicular pathways. To achieve its function, Ykt6 cycles between the cytosol and membrane-bound compartments through reversible lipidation. The mechanism that regulates these transitions is unknown. Ykt6 function is disrupted by α-synuclein, a protein critically implicated in synucleinopathies such as Parkinson’s Disease. Through a multidisciplinary approach, we report that phosphorylation regulated by Ca 2+ signaling drives a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. Phosphorylation is also a critical determinant for Ykt6 protein interactions with functional consequences in the secretory and autophagy pathways under normal and α-synuclein conditions. This work provides a mechanistic insight into Ykt6 regulation with therapeutic implications for synucleinopathies.