Two helices control the dynamic crosstalk between the catalytic domains of LRRK2

Weng, J.-H.; Aoto, P. C.; Lorenz, R.; Wu, J.; Schmidt, S. H.; Manschwetus, J. T.; Kaila-Sharma, P.; Mathea, S.; Knapp, S.; Herberg, F. W.; Taylor, S. S.

doi:10.1101/2021.09.29.462278

bioRxiv · 10.1101/2021.09.29.462278

Two helices control the dynamic crosstalk between the catalytic domains of LRRK2

Weng, J.-H.·Aoto, P. C.·Lorenz, R.·Wu, J.·Schmidt, S. H.·Manschwetus, J. T.·Kaila-Sharma, P.·Mathea, S.·Knapp, S.·Herberg, F. W.·Taylor, S. S.

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Abstract

The two major molecular switches in biology, kinases and GTPases, are both contained in the Parkinsons 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 two helices that shield the kinase domain and regulate LRRK2 conformation and function. One docking helix in COR-B (Dk-Helix) tethers the COR-B domain to the C 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 Dk-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.

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Weng, J.-H., Aoto, P. C., Lorenz, R., Wu, J., Schmidt, S. H., Manschwetus, J. T., Kaila-Sharma, P., Mathea, S., Knapp, S., Herberg, F. W., Taylor, S. S.. 2021-09-29. Two helices control the dynamic crosstalk between the catalytic domains of LRRK2. https://doi.org/10.1101/2021.09.29.462278

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