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| Title | Structural insights into the GTP-driven monomerization and activation of a bacterial LRRK2 homolog using allosteric nanobodies. |
|---|---|
| Journal, issue, pages | Elife, Vol. 13, Year 2024 |
| Publish date | Apr 26, 2024 |
 Authors | Christian Galicia / Giambattista Guaitoli / Marcus Fislage / Christian Johannes Gloeckner / Wim Versées /   |
| 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 ...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. |
 External links | Elife / PubMed:38666771 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.55 - 8.3 Å |
| Structure data |  EMDB-18879: Roco protein from C. tepidum in the GTP state bound to an activating Nanobody  EMDB-18882: Roco protein from C. tepidum in the GTP state bound to the activating Nanobodies NbRoco1 and NbRoco2 EMDB-18884: Ensemble map of the Roco protein from C. tepidum in the GTP state bound to the activating Nanobodies NbRoco1 and NbRoco2 EMDB-18885: Focused map on the LRR domain of the Roco protein from C. tepidum bound to the activating Nanobody NbRoco2 EMDB-18886, PDB-8r4d: |
| Chemicals |  ChemComp-GSP: |
| Source |
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 Keywords |  HYDROLASE / GTPase / Nanobody / Parkinson's Disease / Allostery activator |
