In:
PLOS Biology, Public Library of Science (PLoS), Vol. 20, No. 2 ( 2022-2-22), p. e3001427-
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 (LRRK2 RCKW ). 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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001427
DOI:
10.1371/journal.pbio.3001427.g001
DOI:
10.1371/journal.pbio.3001427.g002
DOI:
10.1371/journal.pbio.3001427.g003
DOI:
10.1371/journal.pbio.3001427.g004
DOI:
10.1371/journal.pbio.3001427.g005
DOI:
10.1371/journal.pbio.3001427.g006
DOI:
10.1371/journal.pbio.3001427.g007
DOI:
10.1371/journal.pbio.3001427.g008
DOI:
10.1371/journal.pbio.3001427.s001
DOI:
10.1371/journal.pbio.3001427.s002
DOI:
10.1371/journal.pbio.3001427.s003
DOI:
10.1371/journal.pbio.3001427.s004
DOI:
10.1371/journal.pbio.3001427.s005
DOI:
10.1371/journal.pbio.3001427.s006
DOI:
10.1371/journal.pbio.3001427.s007
DOI:
10.1371/journal.pbio.3001427.s008
DOI:
10.1371/journal.pbio.3001427.s009
DOI:
10.1371/journal.pbio.3001427.s010
DOI:
10.1371/journal.pbio.3001427.s011
DOI:
10.1371/journal.pbio.3001427.s012
DOI:
10.1371/journal.pbio.3001427.s013
DOI:
10.1371/journal.pbio.3001427.s014
DOI:
10.1371/journal.pbio.3001427.s015
DOI:
10.1371/journal.pbio.3001427.s016
DOI:
10.1371/journal.pbio.3001427.s017
DOI:
10.1371/journal.pbio.3001427.s018
DOI:
10.1371/journal.pbio.3001427.s019
DOI:
10.1371/journal.pbio.3001427.s020
DOI:
10.1371/journal.pbio.3001427.s021
DOI:
10.1371/journal.pbio.3001427.s022
DOI:
10.1371/journal.pbio.3001427.r001
DOI:
10.1371/journal.pbio.3001427.r002
DOI:
10.1371/journal.pbio.3001427.r003
DOI:
10.1371/journal.pbio.3001427.r004
DOI:
10.1371/journal.pbio.3001427.r005
DOI:
10.1371/journal.pbio.3001427.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2126773-X
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