Home > Publications Database > Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism. > print

001     274060
005     20250119000310.0
024 7 _ |a 10.7554/eLife.91083
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037 _ _ |a DZNE-2025-00041
041 _ _ |a English
082 _ _ |a 600
100 1 _ |a Gilsbach, Bernd K
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245 _ _ |a Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.
260 _ _ |a Cambridge
|c 2024
|b eLife Sciences Publications
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520 _ _ |a 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.
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650 _ 7 |a GTPase
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650 _ 7 |a LRRK2
|2 Other
650 _ 7 |a Michaelis–Menten kinetics
|2 Other
650 _ 7 |a PD
|2 Other
650 _ 7 |a biochemistry
|2 Other
650 _ 7 |a chemical biology
|2 Other
650 _ 7 |a negative feedback loop
|2 Other
650 _ 7 |a none
|2 Other
650 _ 7 |a parkinson's disease
|2 Other
650 _ 7 |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
|0 EC 2.7.11.1
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650 _ 7 |a LRRK2 protein, human
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650 _ 7 |a Guanosine Triphosphate
|0 86-01-1
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650 _ 2 |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
|2 MeSH
650 _ 2 |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
|2 MeSH
650 _ 2 |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: chemistry
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Phosphorylation
|2 MeSH
650 _ 2 |a Guanosine Triphosphate: metabolism
|2 MeSH
650 _ 2 |a Kinetics
|2 MeSH
650 _ 2 |a Protein Domains
|2 MeSH
650 _ 2 |a Parkinson Disease: genetics
|2 MeSH
650 _ 2 |a Parkinson Disease: metabolism
|2 MeSH
650 _ 2 |a Feedback, Physiological
|2 MeSH
700 1 _ |a Ho, Franz Y
|b 1
700 1 _ |a Riebenbauer, Benjamin
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700 1 _ |a Zhang, Xiaojuan
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700 1 _ |a Guaitoli, Giambattista
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700 1 _ |a Kortholt, Arjan
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700 1 _ |a Gloeckner, Christian Johannes
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773 _ _ |a 10.7554/eLife.91083
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856 4 _ |y OpenAccess
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