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000274060 1001_ $$0P:(DE-2719)2811745$$aGilsbach, Bernd K$$b0$$eFirst author$$udzne
000274060 245__ $$aIntramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.
000274060 260__ $$aCambridge$$beLife Sciences Publications$$c2024
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000274060 520__ $$aThe 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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000274060 650_7 $$2Other$$aGTPase
000274060 650_7 $$2Other$$aLRRK2
000274060 650_7 $$2Other$$aMichaelis–Menten kinetics
000274060 650_7 $$2Other$$aPD
000274060 650_7 $$2Other$$abiochemistry
000274060 650_7 $$2Other$$achemical biology
000274060 650_7 $$2Other$$anegative feedback loop
000274060 650_7 $$2Other$$anone
000274060 650_7 $$2Other$$aparkinson's disease
000274060 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
000274060 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLRRK2 protein, human
000274060 650_7 $$086-01-1$$2NLM Chemicals$$aGuanosine Triphosphate
000274060 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
000274060 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
000274060 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: chemistry
000274060 650_2 $$2MeSH$$aHumans
000274060 650_2 $$2MeSH$$aPhosphorylation
000274060 650_2 $$2MeSH$$aGuanosine Triphosphate: metabolism
000274060 650_2 $$2MeSH$$aKinetics
000274060 650_2 $$2MeSH$$aProtein Domains
000274060 650_2 $$2MeSH$$aParkinson Disease: genetics
000274060 650_2 $$2MeSH$$aParkinson Disease: metabolism
000274060 650_2 $$2MeSH$$aFeedback, Physiological
000274060 7001_ $$aHo, Franz Y$$b1
000274060 7001_ $$0P:(DE-2719)9000377$$aRiebenbauer, Benjamin$$b2$$udzne
000274060 7001_ $$aZhang, Xiaojuan$$b3
000274060 7001_ $$0P:(DE-2719)2811633$$aGuaitoli, Giambattista$$b4$$udzne
000274060 7001_ $$00000-0001-8174-6397$$aKortholt, Arjan$$b5
000274060 7001_ $$0P:(DE-2719)2811291$$aGloeckner, Christian Johannes$$b6$$eLast author
000274060 773__ $$0PERI:(DE-600)2687154-3$$a10.7554/eLife.91083$$gVol. 12, p. RP91083$$pRP91083$$teLife$$v12$$x2050-084X$$y2024
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