LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains |
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Authors: | Jui-Hung Weng Phillip C. Aoto Robin Lorenz Jian Wu Sven H. Schmidt Jascha T. Manschwetus Pallavi Kaila-Sharma Steve Silletti Sebastian Mathea Deep Chatterjee Stefan Knapp Friedrich W. Herberg Susan S. Taylor |
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Affiliation: | 1. Department of Pharmacology, University of California, San Diego, California, United States of America;2. Department of Biochemistry, University of Kassel, Kassel, Germany;3. Department of Chemistry and Biochemistry, University of California, San Diego, California, United States of America;4. Institute for Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt am Main, Germany; National Cancer Institute, UNITED STATES |
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Abstract: | The 2 major molecular switches in biology, kinases and GTPases, are both contained in the Parkinson disease–related leucine-rich repeat kinase 2 (LRRK2). Using hydrogen–deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations, we generated a comprehensive dynamic allosteric portrait of the C-terminal domains of LRRK2 (LRRK2RCKW). We identified 2 helices that shield the kinase domain and regulate LRRK2 conformation and function. One helix in COR-B (COR-B Helix) tethers the COR-B domain to the αC helix of the kinase domain and faces its activation loop, while the C-terminal helix (Ct-Helix) extends from the WD40 domain and interacts with both kinase lobes. The Ct-Helix and the N-terminus of the COR-B Helix create a “cap” that regulates the N-lobe of the kinase domain. Our analyses reveal allosteric sites for pharmacological intervention and confirm the kinase domain as the central hub for conformational control.The Parkinson’s disease-related protein LRRK2 contains the two major molecular switches in biology; a kinase and a GTPase. This study uses hydrogen-deuterium exchange mass-spectrometry and molecular dynamics simulations to explore the conformational space of the four C-terminal domains of LRRK2, highlighting two essential regulatory helices that control LRRK2 dynamics. |
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