G2385R and I2020T Mutations Increase LRRK2 GTPase Activity.
The LRRK2 mutation is a major causal mutation in familial Parkinson's disease. Although LRRK2 contains functional GTPase and kinase domains and their activities are altered by pathogenic mutations, most studies focused on LRRK2 kinase activity because the most prevalent mutant, G2019S, enhances kinase activity. However, the G2019S mutation is extremely rare in the Asian population. Instead, the G2385R mutation was reported as a major risk factor in the Asian population. Similar to other LRRK2 studies, G2385R studies have also focused on kinase activity. Here, we investigated GTPase activities of G2385R with other LRRK2 mutants, such as G2019S, R1441C, and I2020T, as well as wild type (WT). Our results suggest that both I2020T and G2385R contain GTPase activities stronger than that of WT. A kinase assay using the commercial recombinant proteins showed that I2020T harbored stronger activity, whereas G2385R had weaker activity than that of WT, as reported previously. This is the first report of LRRK2 I2020T and G2385R GTPase activities and shows that most of the LRRK2 mutations that are pathogenic or a risk factor altered either kinase or GTPase activity, suggesting that their physiological consequences are caused by altered enzyme activities.
InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, Sanbondong, Gunposhi, Gyeonggido 15865, Republic of Korea; Department of Molecular and Life Sciences, Hanyang University, Ansanshi, Gyeonggido 15588, Republic of Korea.
Dong Hwan
0000-0003-4938-4108
DH
Ho
Department of Molecular and Life Sciences, Hanyang University, Ansanshi, Gyeonggido 15588, Republic of Korea.
Jihoon
J
Jang
Department of Pharmacology, Ajou University School of Medicine, Suwonshi 16499, Republic of Korea; Neuroscience Graduate Program, Ajou University School of Medicine, Suwonshi 16499, Republic of Korea; Institute for Medical Sciences, Ajou University School of Medicine, Suwonshi 16499, Republic of Korea.
Eun-Hye
EH
Joe
InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, Sanbondong, Gunposhi, Gyeonggido 15865, Republic of Korea; Department of Neurology, Sanbon Medical Center, College of Medicine, Wonkwang University, Sanbondong, Gunposhi, Gyeonggido 15865, Republic of Korea.
Ilhong
I
Son
Department of Molecular and Life Sciences, Hanyang University, Ansanshi, Gyeonggido 15588, Republic of Korea.
Hyemyung
0000-0003-1109-5845
H
Seo
InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, Sanbondong, Gunposhi, Gyeonggido 15865, Republic of Korea.
Wongi
W
Seol
D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000737:chemistry* / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000737:chemistry* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D020558:GTP Phosphohydrolases