negative regulation of peptidyl-tyrosine phosphorylation / osteoclast development / positive regulation of intracellular signal transduction / bone resorption / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of canonical Wnt signaling pathway / non-specific serine/threonine protein kinase / intracellular signal transduction / リン酸化 / protein serine kinase activity ...negative regulation of peptidyl-tyrosine phosphorylation / osteoclast development / positive regulation of intracellular signal transduction / bone resorption / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of canonical Wnt signaling pathway / non-specific serine/threonine protein kinase / intracellular signal transduction / リン酸化 / protein serine kinase activity / protein serine/threonine kinase activity / GTP binding / ミトコンドリア / ATP binding / identical protein binding / metal ion binding / 細胞質基質 類似検索 - 分子機能
C-terminal of Roc (COR) domain / C-terminal of Roc, COR, domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine-rich repeats, bacterial type / ロイシンリッチリピート / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. ...C-terminal of Roc (COR) domain / C-terminal of Roc, COR, domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine-rich repeats, bacterial type / ロイシンリッチリピート / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / ロイシンリッチリピート / Leucine-rich repeat domain superfamily / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / WD40-repeat-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase 類似検索 - ドメイン・相同性
National Institutes of Health/National Cancer Institute (NIH/NCI)
ZIA BC 011744
米国
引用
ジャーナル: Nat Commun / 年: 2023 タイトル: Structure and regulation of full-length human leucine-rich repeat kinase 1. 著者: Riley D Metcalfe / Juliana A Martinez Fiesco / Luis Bonet-Ponce / Jillian H Kluss / Mark R Cookson / Ping Zhang / 要旨: The human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases, which regulate fundamental cellular processes and have been implicated in human ...The human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases, which regulate fundamental cellular processes and have been implicated in human disease. Structures of LRRK2 have recently been determined, but the structure and molecular mechanisms regulating the activity of the LRRK1 as well as differences in the regulation of LRRK1 and LRRK2 remain unclear. Here, we report a cryo-EM structure of the LRRK1 monomer and a lower-resolution cryo-EM map of the LRRK1 dimer. The monomer structure, in which the kinase is in an inactive conformation, reveals key interdomain interfaces that control kinase activity as we validate experimentally. Both the LRRK1 monomer and dimer are structurally distinct compared to LRRK2. Overall, our results provide structural insights into the activation of the human LRRKs, which advance our understanding of their physiological and pathological roles.