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@ARTICLE{Gilsbach:274060,
      author       = {Gilsbach, Bernd K and Ho, Franz Y and Riebenbauer, Benjamin
                      and Zhang, Xiaojuan and Guaitoli, Giambattista and Kortholt,
                      Arjan and Gloeckner, Christian Johannes},
      title        = {{I}ntramolecular feedback regulation of the {LRRK}2 {R}oc
                      {G} domain by a {LRRK}2 kinase-dependent mechanism.},
      journal      = {eLife},
      volume       = {12},
      issn         = {2050-084X},
      address      = {Cambridge},
      publisher    = {eLife Sciences Publications},
      reportid     = {DZNE-2025-00041},
      pages        = {RP91083},
      year         = {2024},
      abstract     = {The Parkinson's disease (PD)-linked protein Leucine-Rich
                      Repeat Kinase 2 (LRRK2) consists of seven domains, including
                      a kinase and a Roc G domain. Despite the availability of
                      several high-resolution structures, the dynamic regulation
                      of its unique intramolecular domain stack is nevertheless
                      still not well understood. By in-depth biochemical analysis,
                      assessing the Michaelis-Menten kinetics of the Roc G domain,
                      we have confirmed that LRRK2 has, similar to other Roco
                      protein family members, a KM value of LRRK2 that lies within
                      the range of the physiological GTP concentrations within the
                      cell. Furthermore, the R1441G PD variant located within a
                      mutational hotspot in the Roc domain showed an increased
                      catalytic efficiency. In contrast, the most common PD
                      variant G2019S, located in the kinase domain, showed an
                      increased KM and reduced catalytic efficiency, suggesting a
                      negative feedback mechanism from the kinase domain to the G
                      domain. Autophosphorylation of the G1+2 residue (T1343) in
                      the Roc P-loop motif is critical for this phosphoregulation
                      of both the KM and the kcat values of the Roc-catalyzed GTP
                      hydrolysis, most likely by changing the monomer-dimer
                      equilibrium. The LRRK2 T1343A variant has a similar
                      increased kinase activity in cells compared to G2019S and
                      the double mutant T1343A/G2019S has no further increased
                      activity, suggesting that T1343 is crucial for the negative
                      feedback in the LRRK2 signaling cascade. Together, our data
                      reveal a novel intramolecular feedback regulation of the
                      LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.
                      Interestingly, PD mutants differently change the kinetics of
                      the GTPase cycle, which might in part explain the difference
                      in penetrance of these mutations in PD patients.},
      keywords     = {Leucine-Rich Repeat Serine-Threonine Protein Kinase-2:
                      metabolism / Leucine-Rich Repeat Serine-Threonine Protein
                      Kinase-2: genetics / Leucine-Rich Repeat Serine-Threonine
                      Protein Kinase-2: chemistry / Humans / Phosphorylation /
                      Guanosine Triphosphate: metabolism / Kinetics / Protein
                      Domains / Parkinson Disease: genetics / Parkinson Disease:
                      metabolism / Feedback, Physiological / GTPase (Other) /
                      LRRK2 (Other) / Michaelis–Menten kinetics (Other) / PD
                      (Other) / biochemistry (Other) / chemical biology (Other) /
                      negative feedback loop (Other) / none (Other) / parkinson's
                      disease (Other) / Leucine-Rich Repeat Serine-Threonine
                      Protein Kinase-2 (NLM Chemicals) / LRRK2 protein, human (NLM
                      Chemicals) / Guanosine Triphosphate (NLM Chemicals)},
      cin          = {AG Gloeckner / AG Gasser},
      ddc          = {600},
      cid          = {I:(DE-2719)1210007 / I:(DE-2719)1210000},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39699947},
      pmc          = {pmc:PMC11658767},
      doi          = {10.7554/eLife.91083},
      url          = {https://pub.dzne.de/record/274060},
}