Aufsatz in einer Fachzeitschrift
LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains
Details zur Publikation
Autor(inn)en: | Weng, J.; Aoto, P.; Lorenz, R.; Wu, J.; Schmidt, S.; Manschwetus, J.; Kaila-Sharma, P.; Silletti, S.; Mathea, S.; Chatterjee, D.; Knapp, S.; Herberg, F.; Taylor, S. |
Publikationsjahr: | 2022 |
Zeitschrift: | PLoS Biology |
Seitenbereich: | e3001427 |
Jahrgang/Band : | 20 |
Heftnummer: | 2 |
ISSN: | 1544-9173 |
eISSN: | 1545-7885 |
DOI-Link der Erstveröffentlichung: |
Zusammenfassung, 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 \textgreekaC 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 {\textquotedbl}cap{\textquotedbl} 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.
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 \textgreekaC 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 {\textquotedbl}cap{\textquotedbl} 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.
