Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2

被引：32

作者：

Schmidt, Sven H. ^{[1
]}

Weng, Jui-Hung ^{[2
]}

Aoto, Phillip C. ^{[2
,3
]}

Boassa, Daniela ^{[4
,5
]}

Mathea, Sebastian ^{[6
]}

Silletti, Steve ^{[3
]}

Hu, Junru ^{[4
,5
]}

Wallbott, Maximilian ^{[1
]}

Komives, Elizabeth A. ^{[3
]}

Knapp, Stefan ^{[6
,7
]}

Herberg, Friedrich W. ^{[1
]}

Taylor, Susan S. ^{[2
,3
]}

机构：

[1] Univ Kassel, Dept Biochem, D-34132 Kassel, Germany

[2] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Natl Ctr Microscopy & Imaging Res, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[6] Goethe Univ Frankfurt, Inst Pharmaceut Chem, D-60438 Frankfurt, Germany

[7] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, Struct Genom Consortium, D-60438 Frankfurt, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2021年 / 118卷 / 23期

基金：

加拿大创新基金会;

关键词：

leucine-rich repeat kinase 2 (LRRK2); hydrogen-deuterium exchange mass spectrometry (HDX-MS); Gaussian accelerated molecular dynamics; kinase regulation; Parkinson's disease; 14-3-3; BINDING; RAF; MUTATIONS; PATHWAY; PHOSPHORYLATION; LOCALIZATION; INHIBITOR; MECHANISM; ENHANCE; LEADS;

D O I：

10.1073/pnas.2100844118

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

To explore how pathogenic mutations of the multidomain leucinerich repeat kinase 2 (LRRK2) hijack its finely tuned activation process and drive Parkinson's disease (PD), we used a multitiered approach. Most mutations mimic Rab-mediated activation by "unleashing" kinase activity, and many, like the kinase inhibitor MLi-2, trap LRRK2 onto microtubules. Here we mimic activation by simply deleting the inhibitory N-terminal domains and then characterize conformational changes induced by MLi-2 and PD mutations. After confirming that LRRK2(RCKW) retains full kinase activity, we used hydrogen-deuterium exchange mass spectrometry to capture breathing dynamics in the presence and absence of MLi-2. Solvent-accessible regions throughout the entire protein are reduced by MLi-2 binding. With molecular dynamics simulations, we created a dynamic portrait of LRRK2(RCKW) and demonstrate the consequences of kinase domain mutations. Although all domains contribute to regulating kinase activity, the kinase domain, driven by the DYG(psi) motif, is the allosteric hub that drives LRRK2 regulation.

引用

页数：12