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

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dc.contributor.authorMcGrath, Kaitlyn
dc.contributor.authorAgarwal, Shivani
dc.contributor.authorTonelli, Marco
dc.contributor.authorDergai, Mykola
dc.contributor.authorGaeta, Anthony L.
dc.contributor.authorShum, Andrew K.
dc.contributor.authorLacoste, Jessica
dc.contributor.authorZhang, Yongbo
dc.contributor.authorWen, Wenyu
dc.contributor.authorChung, Daayun
dc.contributor.authorWiersum, Grant
dc.contributor.authorShevade, Aishwarya
dc.contributor.authorZaichick, Sofia
dc.contributor.authorvan Rossum, Damian B.
dc.contributor.authorShuvalova, Ludmilla
dc.contributor.authorSavas, Jeffrey N.
dc.contributor.authorKuchin, Sergei
dc.contributor.authorTaipale, Mikko
dc.contributor.authorCaldwell, Kim A.
dc.contributor.authorCaldwell, Guy A.
dc.contributor.authorFasshauer, Dirk
dc.contributor.authorCaraveo, Gabriela
dc.contributor.otherNorthwestern University
dc.contributor.otherFeinberg School of Medicine
dc.contributor.otherUniversity of Wisconsin Madison
dc.contributor.otherUniversity of Lausanne
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.contributor.otherUniversity of Toronto
dc.contributor.otherFudan University
dc.contributor.otherUniversity of Wisconsin Milwaukee
dc.contributor.otherPennsylvania State University
dc.contributor.otherPenn State Health
dc.contributor.otherUniversity of Alabama Birmingham
dc.contributor.otherUniversity of Pennsylvania
dc.date.accessioned2023-09-29T12:45:05Z
dc.date.available2023-09-29T12:45:05Z
dc.date.issued2021
dc.description.abstractYkt6 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.en_US
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.citationMcGrath, 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., … Caraveo, G. (2021). A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6. In Proceedings of the National Academy of Sciences (Vol. 118, Issue 12). Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2016730118
dc.identifier.doi10.1073/pnas.2016730118
dc.identifier.orcidhttps://orcid.org/0000-0002-0798-4730
dc.identifier.orcidhttps://orcid.org/0000-0002-1040-4282
dc.identifier.orcidhttps://orcid.org/0000-0002-8216-1371
dc.identifier.orcidhttps://orcid.org/0000-0002-8283-9090
dc.identifier.orcidhttps://orcid.org/0000-0003-2959-7990
dc.identifier.orcidhttps://orcid.org/0000-0002-7700-5745
dc.identifier.orcidhttps://orcid.org/0000-0003-3811-1761
dc.identifier.urihttps://ir.ua.edu/handle/123456789/12374
dc.languageEnglish
dc.language.isoen_US
dc.publisherNational Academy of the Sciences
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectSNARE
dc.subjectcalcineurin
dc.subjectParkinson's disease
dc.subjectconformation
dc.subjectYkt6
dc.subjectMultidisciplinary Sciences
dc.titleA conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6en_US
dc.typeArticle
dc.typetext

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