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000269345 1001_ $$00000-0001-6080-7533$$aGalicia, Christian$$b0
000269345 245__ $$aStructural insights into the GTP-driven monomerization and activation of a bacterial LRRK2 homolog using allosteric nanobodies.
000269345 260__ $$aCambridge$$beLife Sciences Publications$$c2024
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000269345 520__ $$aRoco 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: NbRoco1 and NbRoco2. 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 NbRoco1 and NbRoco2 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.
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000269345 650_7 $$2Other$$aLRRK2
000269345 650_7 $$2Other$$aParkinson's disease
000269345 650_7 $$2Other$$aallosteric mechanism
000269345 650_7 $$2Other$$acryo-EM
000269345 650_7 $$2Other$$amolecular biophysics
000269345 650_7 $$2Other$$ananobodies
000269345 650_7 $$2Other$$anone
000269345 650_7 $$2Other$$astructural biology
000269345 650_7 $$2NLM Chemicals$$aSingle-Domain Antibodies
000269345 650_7 $$086-01-1$$2NLM Chemicals$$aGuanosine Triphosphate
000269345 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
000269345 650_7 $$2NLM Chemicals$$aBacterial Proteins
000269345 650_2 $$2MeSH$$aCryoelectron Microscopy
000269345 650_2 $$2MeSH$$aSingle-Domain Antibodies: metabolism
000269345 650_2 $$2MeSH$$aSingle-Domain Antibodies: chemistry
000269345 650_2 $$2MeSH$$aGuanosine Triphosphate: metabolism
000269345 650_2 $$2MeSH$$aGuanosine Triphosphate: chemistry
000269345 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
000269345 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: chemistry
000269345 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
000269345 650_2 $$2MeSH$$aBacterial Proteins: metabolism
000269345 650_2 $$2MeSH$$aBacterial Proteins: chemistry
000269345 650_2 $$2MeSH$$aBacterial Proteins: genetics
000269345 650_2 $$2MeSH$$aProtein Conformation
000269345 650_2 $$2MeSH$$aAllosteric Regulation
000269345 650_2 $$2MeSH$$aModels, Molecular
000269345 650_2 $$2MeSH$$aProtein Multimerization
000269345 650_2 $$2MeSH$$aHumans
000269345 7001_ $$0P:(DE-2719)2811633$$aGuaitoli, Giambattista$$b1$$udzne
000269345 7001_ $$00000-0002-2527-2657$$aFislage, Marcus$$b2
000269345 7001_ $$0P:(DE-2719)2811291$$aGloeckner, Christian Johannes$$b3
000269345 7001_ $$00000-0002-4695-696X$$aVersées, Wim$$b4
000269345 773__ $$0PERI:(DE-600)2687154-3$$a10.7554/eLife.94503$$gVol. 13, p. RP94503$$pRP94503$$teLife$$v13$$x2050-084X$$y2024
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