Abstract
Mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of familial Parkinson's disease (PD). Recently, we showed that a disease-associated mutation R1441H rendered the GTPase domain of LRRK2 catalytically less active and thereby trapping it in a more persistently "on" conformation. However, the mechanism involved and characteristics of this on conformation remained unknown. Here, we report that the Ras of complex protein (ROC) domain of LRRK2 exists in a dynamic dimer-monomer equilibrium that is oppositely driven by GDP and GTP binding. We also observed that the PD-associated mutations at residue 1441 impair this dynamic and shift the conformation of ROC to a GTP-bound-like monomeric conformation. Moreover, we show that residue Arg-1441 is critical for regulating the conformational dynamics of ROC. In summary, our results reveal that the PD-associated substitutions at Arg-1441 of LRRK2 alter monomer-dimer dynamics and thereby trap its GTPase domain in an activated state.
References
Jan 15, 2002·Journal of Biomolecular Screening·M W PantolianoF R Salemme
Nov 16, 2004·Neuron·Coro Paisán-RuízAndrew B Singleton
Nov 16, 2004·Neuron·Alexander ZimprichThomas Gasser
Apr 18, 2006·Trends in Neurosciences·Ignacio F MataKathleen A Gallo
Jun 2, 2006·Genome Biology·Gregory A Petsko
Jun 6, 2006·Neurobiology of Disease·Elisa GreggioMark R Cookson
Jan 4, 2007·Human Molecular Genetics·Andrew B WestTed M Dawson
Jan 31, 2007·Biochemistry·Genta ItoTakeshi Iwatsubo
Apr 20, 2007·Biochemical and Biophysical Research Communications·Patrick A LewisMark R Cookson
Aug 21, 2007·Experimental Cell Research·Luxuan GuoShu G Chen
Oct 20, 2007·Journal of Neurochemistry·Qiang LiXing-Zhen Chen
Dec 22, 2007·Neuro-Signals·Benoit I Giasson, Vivianna M Van Deerlin
Sep 29, 2009·Biochimica Et Biophysica Acta·Yongchao LiJunpeng Deng
Aug 11, 2010·Progress in Brain Research·Abid OueslatiHilal A Lashuel
Nov 23, 2010·Nature Reviews. Neuroscience·Mark R Cookson
Feb 11, 2014·Proceedings of the National Academy of Sciences of the United States of America·Alexandria BeilinaMark R Cookson
Mar 5, 2014·Proceedings of the National Academy of Sciences of the United States of America·Jingling LiaoQuyen Q Hoang
Sep 24, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Zhiyong LiuAndrew B West
Oct 19, 2017·Nature Communications·Egon DeyaertWim Versées
Dec 20, 2018·International Journal of Molecular Sciences·Jingling Liao, Quyen Q Hoang
Citations
Mar 14, 2020·The Biochemical Journal·Margaux LeemansWim Versées
Apr 23, 2020·Frontiers in Neuroscience·Jascha T ManschwetusFriedrich W Herberg
Oct 21, 2020·Biochemical Society Transactions·Ahmed SolimanArjan Kortholt
Oct 28, 2020·Cells·Lucia IannottaElisa Greggio
Feb 3, 2021·Molecular and Cellular Biology·Ahsan UsmaniAnnie Hiniker
May 26, 2021·Molecular Neurodegeneration·Souvarish SarkarMel B Feany
Sep 10, 2021·ACS Chemical Biology·Leah G HeltonEileen J Kennedy