PT  - JOURNAL ARTICLE
AU  - Schmidt, Sven H.
AU  - Weng, Jui-Hung
AU  - Aoto, Phillip C.
AU  - Boassa, Daniela
AU  - Mathea, Sebastian
AU  - Silletti, Steven
AU  - Hu, Junru
AU  - Wallbott, Maximilian
AU  - Komives, Elizabeth A
AU  - Knapp, Stefan
AU  - Herberg, Friedrich W.
AU  - Taylor, Susan S.
TI  - Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2
AID  - 10.1101/2020.07.13.198069
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.13.198069
4099  - http://biorxiv.org/content/early/2020/07/14/2020.07.13.198069.short
4100  - http://biorxiv.org/content/early/2020/07/14/2020.07.13.198069.full
AB  - 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 StatementThe authors have declared no competing interest.