biostudies-literatureGilsbach BKMichael J. Fox Foundation for Parkinson's ResearchRP91083https://www.ebi.ac.uk/biostudies/studies/S-EPMC11658767biostudies-literatureUnknown12The 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 K_M 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 teLifeIntramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.PMC116587678068.04Gloeckner CJGilsbach BKGuaitoli GHo FYKortholt AZhang XRiebenbauer BfalseIntramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.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 K_M 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 t2024-01-01T00:00:00Z2024 Dec2026-06-01T19:41:11.721Z2025-04-06T22:16:04.084ZS-EPMC116587673969994710.7554/eLife.91083