14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization.

The Biochemical Journal
R Jeremy NicholsDario R Alessi

Abstract

LRRK2 (leucine-rich repeat protein kinase 2) is mutated in a significant number of Parkinson's disease patients, but still little is understood about how it is regulated or functions. In the present study we have demonstrated that 14-3-3 protein isoforms interact with LRRK2. Consistent with this, endogenous LRRK2 isolated from Swiss 3T3 cells or various mouse tissues is associated with endogenous 14-3-3 isoforms. We have established that 14-3-3 binding is mediated by phosphorylation of LRRK2 at two conserved residues (Ser910 and Ser935) located before the leucine-rich repeat domain. Our results suggests that mutation of Ser910 and/or Ser935 to disrupt 14-3-3 binding does not affect intrinsic protein kinase activity, but induces LRRK2 to accumulate within discrete cytoplasmic pools, perhaps resembling inclusion bodies. To investigate links between 14-3-3 binding and Parkinson's disease, we studied how 41 reported mutations of LRRK2 affected 14-3-3 binding and cellular localization. Strikingly, we found that five of the six most common pathogenic mutations (R1441C, R1441G, R1441H, Y1699C and I2020T) display markedly reduced phosphorylation of Ser910/Ser935 thereby disrupting interaction with 14-3-3. We have also demonstrated that...Continue Reading

References

May 26, 1999·The Plant Journal : for Cell and Molecular Biology·G MoorheadC MacKintosh
Sep 3, 2003·Nature Reviews. Neuroscience·Daniela BergOlaf Riess
Nov 16, 2004·Neuron·Coro Paisán-RuízAndrew B Singleton
Aug 13, 2005·The EMBO Journal·Shigeto SatoKeiji Tanaka
Nov 5, 2005·Proceedings of the National Academy of Sciences of the United States of America·Andrew B WestTed M Dawson
Dec 15, 2005·Proceedings of the National Academy of Sciences of the United States of America·Wanli W SmithChristopher A Ross
Apr 18, 2006·Trends in Neurosciences·Ignacio F MataKathleen A Gallo
Jun 6, 2006·Neurobiology of Disease·Elisa GreggioMark R Cookson
Sep 14, 2006·Journal of Cell Science·Olga GöranssonDario R Alessi
Mar 14, 2007·Archives of Neurology·Suzanne LesageMarc Vérin
Mar 28, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Lizhen WangHuaibin Cai
Jun 10, 2008·Lancet Neurology·Daniel G HealyUNKNOWN International LRRK2 Consortium
Nov 1, 2008·Biochimica Et Biophysica Acta·Saskia Biskup, Andrew B West
Aug 4, 2009·Molecular & Cellular Proteomics : MCP·Fanny DuboisCarol MacKintosh
Aug 12, 2009·Proceedings of the National Academy of Sciences of the United States of America·Youren TongJie Shen
Sep 8, 2009·Biochemical and Biophysical Research Communications·Elisa GreggioMark R Cookson
Sep 11, 2009·The Biochemical Journal·R Jeremy NicholsDario R Alessi
Oct 7, 2009·The FEBS Journal·Vasanti S Anand, Steven P Braithwaite
Jul 3, 2010·The Journal of Biological Chemistry·Xiaojie LiValina L Dawson
Dec 15, 2010·Cell Death & Disease·T A YacoubianD G Standaert

❮ Previous
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Citations

Aug 22, 2013·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Liang HuangHoward J Federoff
Jun 17, 2011·Expert Reviews in Molecular Medicine·Azad Kumar, Mark R Cookson
Oct 19, 2012·Nature·Guang-Hui LiuJuan Carlos Izpisua Belmonte
Apr 2, 2011·The Journal of Biological Chemistry·Diane ChanBenjamin Wolozin
Nov 29, 2011·The Journal of Biological Chemistry·Arjan KortholtPeter J M van Haastert
Jun 28, 2012·Human Molecular Genetics·Tatiana D PapkovskaiaJ Mark Cooper
Jul 28, 2013·Human Molecular Genetics·Kyle B FraserAndrew B West
Aug 17, 2011·Cold Spring Harbor Perspectives in Biology·Daryl A BoscoDagmar Ringe
Mar 7, 2012·Cold Spring Harbor Perspectives in Medicine·Lauren R Kett, William T Dauer
May 19, 2012·Journal of Neuroinflammation·Elisa GreggioLuigi Bubacco
Jun 30, 2011·PloS One·Laura de Yñigo-MojadoJames D Sutherland
May 26, 2012·PloS One·Heidi M B LesscherLouk J M J Vanderschuren
May 24, 2011·Parkinson's Disease·Tianxia LiWanli W Smith
Jan 1, 2014·Molekuliarnaia biologiia·S N PchelinaT S Usenko
Dec 24, 2013·BioMed Research International·Tadayuki ShimadaKanato Yamagata
May 9, 2012·Future Neurology·Guoxiang LiuHuaibin Cai
Jun 5, 2013·Neurochemical Research·Hardy J Rideout, Leonidas Stefanis
Dec 20, 2013·Proceedings of the National Academy of Sciences of the United States of America·Kathrin MudaFriedrich W Herberg
Feb 11, 2014·Proceedings of the National Academy of Sciences of the United States of America·Alexandria BeilinaMark R Cookson
Jun 7, 2011·Annual Review of Genomics and Human Genetics·Ian MartinTed M Dawson
Apr 1, 2014·Human Molecular Genetics·Jason SchapanskyMatthew J LaVoie
Jun 25, 2014·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Iakov N Rudenko, Mark R Cookson
Mar 8, 2011·Nature Chemical Biology·Xianming DengNathanael S Gray
Jan 10, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Gaia SkibinskiSteven Finkbeiner
Nov 8, 2015·Human Molecular Genetics·Nicholas J LavalleyTalene A Yacoubian
Mar 26, 2016·Frontiers in Molecular Neuroscience·Jonathon Nixon-AbellKirsten Harvey
Nov 15, 2014·Molecular Neurobiology·A R EstevesS M Cardoso
Aug 14, 2013·The Biochemical Journal·Evy LobbestaelJean-Marc Taymans
Sep 20, 2012·Biochemical Society Transactions·Jean-Marc Taymans
Sep 20, 2012·Biochemical Society Transactions·Laura Civiero, Luigi Bubacco
Sep 20, 2012·Biochemical Society Transactions·Evy LobbestaelJean-Marc Taymans

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Methods Mentioned

BETA
GTPase
transfection
transfections
immunoprecipitation
electrophoresis
co-immunoprecipitation
confocal microscopy

Software Mentioned

Matrix Science
MaxQuant
Mascot

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