8R4C

LRR domain of Roco protein from C. tepidum bound to the activating Nanobody NbRoco2

8R4C の概要

• エントリーDOI: 10.2210/pdb8r4c/pdb
• 関連するPDBエントリー: 8R4B
• EMDBエントリー: 18879 18884 18885
• 分子名称: NbRoco2, Rab family protein (2 entities in total)
• 機能のキーワード: gtpase, nanobody, parkinson's disease, allostery activator, hydrolase
• 由来する生物種: Lama glama; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 138494.20

構造登録者

Galicia, C.,Versees, W. (登録日: 2023-11-13, 公開日: 2024-05-01, 最終更新日: 2024-05-15)

主引用文献

Galicia, C.,Guaitoli, G.,Fislage, M.,Gloeckner, C.J.,Versees, W.
Structural insights into the GTP-driven monomerization and activation of a bacterial LRRK2 homolog using allosteric nanobodies.
Elife, 13:-, 2024

PubMed Abstract: Roco proteins entered the limelight after mutations in human LRRK2 were identified as a major cause of familial Parkinson's disease. LRRK2 is a large and complex protein combining a GTPase and protein kinase activity, and disease mutations increase the kinase activity, while presumably decreasing the GTPase activity. Although a cross-communication between both catalytic activities has been suggested, the underlying mechanisms and the regulatory role of the GTPase domain remain unknown. Several structures of LRRK2 have been reported, but structures of Roco proteins in their activated GTP-bound state are lacking. Here, we use single-particle cryo-electron microscopy to solve the structure of a bacterial Roco protein (CtRoco) in its GTP-bound state, aided by two conformation-specific nanobodies: Nb and Nb. This structure presents CtRoco in an active monomeric state, featuring a very large GTP-induced conformational change using the LRR-Roc linker as a hinge. Furthermore, this structure shows how Nb and Nb collaborate to activate CtRoco in an allosteric way. Altogether, our data provide important new insights into the activation mechanism of Roco proteins, with relevance to LRRK2 regulation, and suggest new routes for the allosteric modulation of their GTPase activity.

PubMed: 38666771
DOI: 10.7554/eLife.94503

実験手法

ELECTRON MICROSCOPY (3.55 Å)