RT Journal Article
SR Electronic
T1 Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.13.198069
DO 10.1101/2020.07.13.198069
A1 Schmidt, Sven H.
A1 Weng, Jui-Hung
A1 Aoto, Phillip C.
A1 Boassa, Daniela
A1 Mathea, Sebastian
A1 Silletti, Steven
A1 Hu, Junru
A1 Wallbott, Maximilian
A1 Komives, Elizabeth A
A1 Knapp, Stefan
A1 Herberg, Friedrich W.
A1 Taylor, Susan S.
YR 2020
UL http://biorxiv.org/content/early/2020/07/14/2020.07.13.198069.abstract
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.