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

Details

Serval ID
serval:BIB_F26C5AEBA233
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
McGrath K., Agarwal S., Tonelli M., Dergai M., Gaeta A.L., Shum A.K., Lacoste J., Zhang Y., Wen W., Chung D., Wiersum G., Shevade A., Zaichick S., van Rossum D.B., Shuvalova L., Savas J.N., Kuchin S., Taipale M., Caldwell K.A., Caldwell G.A., Fasshauer D., Caraveo G.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
23/03/2021
Peer-reviewed
Oui
Volume
118
Number
12
Pages
e2016730118
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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 Ca <sup>2+</sup> 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
Parkinson’s disease, SNARE, Ykt6, calcineurin, conformation
Pubmed
Open Access
Yes
Create date
27/03/2021 16:34
Last modification date
02/04/2021 6:35
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