Einzeltreffer — DigiBib

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 2+ 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.

Competing Interests: The authors declare no competing interest.

Titel:	A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6.
Autor/in / Beteiligte Person:	McGrath, K ; Agarwal, S ; Tonelli, M ; Dergai, M ; Gaeta, AL ; Shum, AK ; Lacoste, J ; Zhang, Y ; Wen, W ; Chung, D ; Wiersum, G ; Shevade, A ; Zaichick, S ; van Rossum DB ; Shuvalova, L ; Savas, JN ; Kuchin, S ; Taipale, M ; Caldwell, KA ; Caldwell, GA ; Fasshauer, D ; Caraveo, G
Link:	Full Text Finder (Volltext)
Zeitschrift:	Proceedings of the National Academy of Sciences of the United States of America, Jg. 118 (2021-03-23), Heft 12
Veröffentlichung:	Washington, DC : National Academy of Sciences, 2021
Medientyp:	academicJournal
ISSN:	1091-6490 (electronic)
DOI:	10.1073/pnas.2016730118
Schlagwort:	Amino Acids Autophagy Carrier Proteins chemistry Carrier Proteins metabolism Cell Membrane metabolism Evolution, Molecular Phosphorylation Protein Binding Protein Interaction Domains and Motifs R-SNARE Proteins genetics Structure-Activity Relationship Conserved Sequence Models, Molecular Protein Conformation R-SNARE Proteins chemistry R-SNARE Proteins metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural Language: English [Proc Natl Acad Sci U S A] 2021 Mar 23; Vol. 118 (12). MeSH Terms: Conserved Sequence* ; Models, Molecular* ; Protein Conformation* ; R-SNARE Proteins / chemistry ; R-SNARE Proteins / metabolism ; Amino Acids ; Autophagy ; Carrier Proteins / chemistry ; Carrier Proteins / metabolism ; Cell Membrane / metabolism ; Evolution, Molecular ; Phosphorylation ; Protein Binding ; Protein Interaction Domains and Motifs ; R-SNARE Proteins / genetics ; Structure-Activity Relationship References: G3 (Bethesda). 2015 Jul 14;5(9):1879-87. (PMID: 26175450) ; PLoS Genet. 2017 Apr 12;13(4):e1006698. (PMID: 28403141) ; Neuron. 2019 Dec 4;104(5):869-884.e11. (PMID: 31648898) ; Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2559-63. (PMID: 8096639) ; Science. 2006 Jul 21;313(5785):324-8. (PMID: 16794039) ; Biomolecules. 2020 Nov 16;10(11):. (PMID: 33207719) ; EMBO J. 2020 Apr 15;39(8):e104120. (PMID: 32128853) ; EMBO Rep. 2020 Dec 3;21(12):e50733. (PMID: 33025734) ; Dev Cell. 2019 Apr 8;49(1):130-144.e6. (PMID: 30827897) ; J Mol Biol. 2008 Apr 11;377(5):1334-45. (PMID: 18329045) ; Front Physiol. 2017 Jan 20;8:5. (PMID: 28163686) ; Circ Res. 2017 Feb 17;120(4):610-612. (PMID: 28209790) ; Nat Cell Biol. 2012 Oct;14(10):1036-45. (PMID: 22983114) ; Mol Biol Cell. 2002 Oct;13(10):3493-507. (PMID: 12388752) ; Science. 1997 Jun 27;276(5321):2045-7. (PMID: 9197268) ; Science. 2003 Dec 5;302(5651):1772-5. (PMID: 14657500) ; Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4815-20. (PMID: 15044687) ; J Cell Biol. 2018 Oct 1;217(10):3670-3682. (PMID: 30097515) ; J Biol Chem. 2001 Sep 14;276(37):34537-44. (PMID: 11445562) ; Traffic. 2010 Sep;11(9):1191-204. (PMID: 20545907) ; Science. 2003 Oct 31;302(5646):841. (PMID: 14593171) ; PLoS Genet. 2018 Apr 25;14(4):e1007359. (PMID: 29694367) ; Sci Rep. 2016 Aug 05;6:30282. (PMID: 27493064) ; Mol Biol Cell. 2010 Jun 1;21(11):1850-63. (PMID: 20392839) ; Nat Rev Neurosci. 2017 Jan 20;18(2):101-113. (PMID: 28104909) ; Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):E3544-52. (PMID: 25122673) ; Nature. 1997 Oct 23;389(6653):881-4. (PMID: 9349823) ; J Cell Biol. 2010 Sep 20;190(6):1023-37. (PMID: 20855506) ; Traffic. 2008 Sep;9(9):1510-21. (PMID: 18541004) ; Nature. 1997 Aug 28;388(6645):839-40. (PMID: 9278044) ; Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11313-E11322. (PMID: 29229832) ; Nat Genet. 2009 Dec;41(12):1308-12. (PMID: 19915575) ; J Neurosci. 2005 Apr 13;25(15):3801-12. (PMID: 15829632) ; J Biol Chem. 1997 Jul 11;272(28):17776-83. (PMID: 9211930) ; Biochem J. 2004 Dec 1;384(Pt 2):233-7. (PMID: 15479160) ; EMBO J. 2016 Aug 15;35(16):1810-21. (PMID: 27402227) ; Cell. 2012 Dec 7;151(6):1256-69. (PMID: 23217709) ; Cell. 1998 Mar 20;92(6):759-72. (PMID: 9529252) ; Mol Biol Cell. 2003 Feb;14(2):698-720. (PMID: 12589064) ; Mol Biol Cell. 2003 May;14(5):1868-81. (PMID: 12802061) ; Mol Cell. 2010 Feb 12;37(3):383-95. (PMID: 20159557) ; J Cell Biol. 2018 Aug 6;217(8):2633-2645. (PMID: 29789439) ; J Cell Sci. 2006 Jun 1;119(Pt 11):2173-83. (PMID: 16723730) ; Science. 2001 Jul 27;293(5530):698-702. (PMID: 11474112) ; Curr Med Chem. 2019;26(20):3702-3718. (PMID: 29484979) ; Mol Biol Cell. 2002 Sep;13(9):3314-24. (PMID: 12221135) ; Genetics. 2013 Feb;193(2):383-410. (PMID: 23396477) ; J Biol Chem. 2012 Aug 10;287(33):27567-79. (PMID: 22722939) ; Proc Natl Acad Sci U S A. 2018 May 22;115(21):5576-5581. (PMID: 29735704) Grant Information: R01 NS117750 United States NS NINDS NIH HHS; R15 NS104857 United States NS NINDS NIH HHS Contributed Indexing: Keywords: Parkinson’s disease; SNARE; Ykt6; calcineurin; conformation Substance Nomenclature: 0 (Amino Acids) ; 0 (Carrier Proteins) ; 0 (R-SNARE Proteins) ; 0 (YKT6 protein, human) Entry Date(s): Date Created: 20210316 Date Completed: 20210906 Latest Revision: 20221005 Update Code: 20240513 PubMed Central ID: PMC8000380

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