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

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005     20260212170421.0
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|a 10.7554/eLife.91083
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|a pmid:39699947
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037 _ _ |a DZNE-2025-00041
041 _ _ |a English
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100 1 _ |0 P:(DE-2719)2811745
|a Gilsbach, Bernd K
|b 0
|e First author
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245 _ _ |a Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.
260 _ _ |a Cambridge
|b eLife Sciences Publications
|c 2024
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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.
536 _ _ |0 G:(DE-HGF)POF4-352
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|c POF4-352
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650 _ 7 |2 Other
|a GTPase
650 _ 7 |2 Other
|a LRRK2
650 _ 7 |2 Other
|a Michaelis–Menten kinetics
650 _ 7 |2 Other
|a PD
650 _ 7 |2 Other
|a biochemistry
650 _ 7 |2 Other
|a chemical biology
650 _ 7 |2 Other
|a negative feedback loop
650 _ 7 |2 Other
|a none
650 _ 7 |2 Other
|a parkinson's disease
650 _ 7 |0 EC 2.7.11.1
|2 NLM Chemicals
|a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
650 _ 7 |0 EC 2.7.11.1
|2 NLM Chemicals
|a LRRK2 protein, human
650 _ 7 |0 86-01-1
|2 NLM Chemicals
|a Guanosine Triphosphate
650 _ 2 |2 MeSH
|a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
650 _ 2 |2 MeSH
|a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
650 _ 2 |2 MeSH
|a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: chemistry
650 _ 2 |2 MeSH
|a Humans
650 _ 2 |2 MeSH
|a Phosphorylation
650 _ 2 |2 MeSH
|a Guanosine Triphosphate: metabolism
650 _ 2 |2 MeSH
|a Kinetics
650 _ 2 |2 MeSH
|a Protein Domains
650 _ 2 |2 MeSH
|a Parkinson Disease: genetics
650 _ 2 |2 MeSH
|a Parkinson Disease: metabolism
650 _ 2 |2 MeSH
|a Feedback, Physiological
700 1 _ |a Ho, Franz Y
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700 1 _ |0 P:(DE-2719)9000377
|a Riebenbauer, Benjamin
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700 1 _ |a Zhang, Xiaojuan
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700 1 _ |0 P:(DE-2719)2811633
|a Guaitoli, Giambattista
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700 1 _ |0 0000-0001-8174-6397
|a Kortholt, Arjan
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700 1 _ |0 P:(DE-2719)2811291
|a Gloeckner, Christian Johannes
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|e Last author
773 _ _ |0 PERI:(DE-600)2687154-3
|a 10.7554/eLife.91083
|g Vol. 12, p. RP91083
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