LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains

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

doi:10.1371/journal.pbio.3001427

LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains

PLoS Biol. 2022 Feb 22;20(2):e3001427. doi: 10.1371/journal.pbio.3001427. eCollection 2022 Feb.

Affiliations

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Allosteric Site
Catalytic Domain*
Deuterium Exchange Measurement / methods
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / chemistry*
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
Mass Spectrometry / methods
Molecular Dynamics Simulation*
Mutation
Protein Binding
Protein Conformation*

Substances

Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

Grants and funding

This work was supported by Michael J. Fox Foundation Grant 11425 (https://www.michaeljfox.org/) (to S.S.T., and F.W.H.), and Ruth L. Kirschstein National Research Service Award NIH/National Cancer Institute T32 CA009523 (to P.C.A.). JTM was supported by an Otto-Braun Fund Predoctoral Fellowship (B. Braun Melsungen AG). S.M. and S.K. are grateful for support from the Deutsche Forschungsgemeinschaft (DFG) (HE 1818/11) and Structural Genomics Consortium (SGC), a registered charity that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (875510), Janssen, Merck KGaA Darmstadt Germany, Merck Sharp and Dohme (MSD), Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation. The Synapt G2Si HD/X mass spectrometer was obtained from shared instrumentation NIH Grant S10 OD016234 (to S.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.