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Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2

Sven H. Schmidt, View ORCID ProfileJui-Hung Weng, View ORCID ProfilePhillip C. Aoto, Daniela Boassa, View ORCID ProfileSebastian Mathea, Steven Silletti, Junru Hu, Maximilian Wallbott, View ORCID ProfileElizabeth A Komives, View ORCID ProfileStefan Knapp, View ORCID ProfileFriedrich W. Herberg, View ORCID ProfileSusan S. Taylor
doi: https://doi.org/10.1101/2020.07.13.198069
Sven H. Schmidt
1Department of Biochemistry, University of Kassel, 34132 Kassel, Germany
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Jui-Hung Weng
2Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA
3Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA
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Phillip C. Aoto
2Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA
3Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA
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Daniela Boassa
4National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, California 92093, USA
5Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA
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Sebastian Mathea
6Institute for Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany
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  • ORCID record for Sebastian Mathea
Steven Silletti
3Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA
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Junru Hu
4National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, California 92093, USA
5Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA
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Maximilian Wallbott
1Department of Biochemistry, University of Kassel, 34132 Kassel, Germany
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Elizabeth A Komives
3Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA
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  • ORCID record for Elizabeth A Komives
Stefan Knapp
6Institute for Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany
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  • ORCID record for Stefan Knapp
Friedrich W. Herberg
1Department of Biochemistry, University of Kassel, 34132 Kassel, Germany
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  • For correspondence: staylor@ucsd.edu
Susan S. Taylor
2Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA
3Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA
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  • For correspondence: staylor@ucsd.edu
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Abstract

In a multi-tiered approach, we explored how Parkinson’s Disease-related mutations hijack the finely tuned activation process of Leucine-Rich Repeat Kinase 2 (LRRK2) using a construct containing the ROC, Cor, Kinase and WD40 domains (LRRK2RCKW). We hypothesized that the N-terminal domains shield the catalytic domains in an inactive state. PD mutations, type-I LRRK2 inhibitors, or physiological Rab GTPases can unleash the catalytic domains while the active kinase conformation, but not kinase activity, is essential for docking onto microtubules. Mapping solvent accessible regions of LRRK2RCKW employing hydrogen-deuterium exchange mass spectrometry (HDX-MS) revealed how inhibitor binding is sensed by the entire protein. Molecular Dynamics simulations of the kinase domain elucidated differences in conformational dynamics between wt and mutants of the DYGψ motif. While all domains contribute to regulating kinase activity and spatial distribution, the kinase domain, driven by the DYGψ motif, coordinates domain crosstalk and serves as an intrinsic hub for LRRK2 regulation.

Competing Interest Statement

The authors have declared no competing interest.

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Posted July 14, 2020.
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Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2
Sven H. Schmidt, Jui-Hung Weng, Phillip C. Aoto, Daniela Boassa, Sebastian Mathea, Steven Silletti, Junru Hu, Maximilian Wallbott, Elizabeth A Komives, Stefan Knapp, Friedrich W. Herberg, Susan S. Taylor
bioRxiv 2020.07.13.198069; doi: https://doi.org/10.1101/2020.07.13.198069
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Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2
Sven H. Schmidt, Jui-Hung Weng, Phillip C. Aoto, Daniela Boassa, Sebastian Mathea, Steven Silletti, Junru Hu, Maximilian Wallbott, Elizabeth A Komives, Stefan Knapp, Friedrich W. Herberg, Susan S. Taylor
bioRxiv 2020.07.13.198069; doi: https://doi.org/10.1101/2020.07.13.198069

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