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@ARTICLE{Galicia:269345,
      author       = {Galicia, Christian and Guaitoli, Giambattista and Fislage,
                      Marcus and Gloeckner, Christian Johannes and Versées, Wim},
      title        = {{S}tructural insights into the {GTP}-driven monomerization
                      and activation of a bacterial {LRRK}2 homolog using
                      allosteric nanobodies.},
      journal      = {eLife},
      volume       = {13},
      issn         = {2050-084X},
      address      = {Cambridge},
      publisher    = {eLife Sciences Publications},
      reportid     = {DZNE-2024-00514},
      pages        = {RP94503},
      year         = {2024},
      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: 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.},
      keywords     = {Cryoelectron Microscopy / Single-Domain Antibodies:
                      metabolism / Single-Domain Antibodies: chemistry / Guanosine
                      Triphosphate: metabolism / Guanosine Triphosphate: chemistry
                      / Leucine-Rich Repeat Serine-Threonine Protein Kinase-2:
                      metabolism / Leucine-Rich Repeat Serine-Threonine Protein
                      Kinase-2: chemistry / Leucine-Rich Repeat Serine-Threonine
                      Protein Kinase-2: genetics / Bacterial Proteins: metabolism
                      / Bacterial Proteins: chemistry / Bacterial Proteins:
                      genetics / Protein Conformation / Allosteric Regulation /
                      Models, Molecular / Protein Multimerization / Humans / LRRK2
                      (Other) / Parkinson's disease (Other) / allosteric mechanism
                      (Other) / cryo-EM (Other) / molecular biophysics (Other) /
                      nanobodies (Other) / none (Other) / structural biology
                      (Other) / Single-Domain Antibodies (NLM Chemicals) /
                      Guanosine Triphosphate (NLM Chemicals) / Leucine-Rich Repeat
                      Serine-Threonine Protein Kinase-2 (NLM Chemicals) /
                      Bacterial Proteins (NLM Chemicals)},
      cin          = {AG Gloeckner},
      ddc          = {600},
      cid          = {I:(DE-2719)1210007},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38666771},
      pmc          = {pmc:PMC11052575},
      doi          = {10.7554/eLife.94503},
      url          = {https://pub.dzne.de/record/269345},
}