7THZ

Structure of Leucine Rich Repeat Kinase 2's ROC domain interacting with the microtubule facing the plus end

7THZ の概要

• エントリーDOI: 10.2210/pdb7thz/pdb
• EMDBエントリー: 25649 25658 25897 25907
• 分子名称: Leucine-rich repeat serine/threonine-protein kinase 2, GUANOSINE-5'-DIPHOSPHATE (2 entities in total)
• 機能のキーワード: parkinson's disease, microtubule, kinase, gtpase, cytosolic protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22634.96

構造登録者

Matyszewski, M.,Leschziner, A.E. (登録日: 2022-01-12, 公開日: 2022-12-28, 最終更新日: 2024-06-05)

主引用文献

Snead, D.M.,Matyszewski, M.,Dickey, A.M.,Lin, Y.X.,Leschziner, A.E.,Reck-Peterson, S.L.
Structural basis for Parkinson's disease-linked LRRK2's binding to microtubules.
Nat.Struct.Mol.Biol., 29:1196-1207, 2022

PubMed Abstract: Leucine-rich repeat kinase 2 (LRRK2) is one of the most commonly mutated genes in familial Parkinson's disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an association enhanced by PD mutations. We report a cryo-EM structure of the catalytic half of LRRK2, containing its kinase, in a closed conformation, and GTPase domains, bound to microtubules. We also report a structure of the catalytic half of LRRK1, which is closely related to LRRK2 but is not linked to PD. Although LRRK1's structure is similar to that of LRRK2, we find that LRRK1 does not interact with microtubules. Guided by these structures, we identify amino acids in LRRK2's GTPase that mediate microtubule binding; mutating them disrupts microtubule binding in vitro and in cells, without affecting LRRK2's kinase activity. Our results have implications for the design of therapeutic LRRK2 kinase inhibitors.

PubMed: 36510024
DOI: 10.1038/s41594-022-00863-y

実験手法

ELECTRON MICROSCOPY (5 Å)