2007
DOI: 10.1016/j.yexcr.2007.07.007
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The Parkinson’s disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase thatstimulates kinase activity

Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of autosomal dominant Parkinson's disease (PD). LRRK2, a member of the ROCO protein family, contains both Ras GTPase-like (Roc) and kinase (MAPKKK) domains, as well as other functional motifs. Here, we have identified LRRK2 as the first mammalian ROCO protein that is an authentic and functional GTPase, defined by the ability to bind GTP and undergo intrinsic GTP hydrolysis. Furthermore, the Roc domain is sufficient for this native… Show more

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Cited by 198 publications
(246 citation statements)
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References 42 publications
(81 reference statements)
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“…In humans, however, it is unknown whether loss-of-function mutations in LRRK2 lead to dopaminergic cell death. On the contrary, it seems that it is increased/constitutive activity of the LRRK2 protein (West et al 2005;Gloeckner et al 2006;Smith et al 2006;Guo et al 2007;Li et al 2007). In summary, researchers in this field should be very careful before extrapolating results obtained for protostome LRRK genes to humans.…”
Section: Discussionmentioning
confidence: 98%
“…In humans, however, it is unknown whether loss-of-function mutations in LRRK2 lead to dopaminergic cell death. On the contrary, it seems that it is increased/constitutive activity of the LRRK2 protein (West et al 2005;Gloeckner et al 2006;Smith et al 2006;Guo et al 2007;Li et al 2007). In summary, researchers in this field should be very careful before extrapolating results obtained for protostome LRRK genes to humans.…”
Section: Discussionmentioning
confidence: 98%
“…The GTPase activity for N1437H has not been determined, but it has been shown that this mutant has increased GTP binding [13], which is consistent with lower GTPase activity. The reported GTP-binding capacity of R1441C/G and Y1699C is less consistent, with some reports of an increase and others finding no change in GTP binding [45,47,48]. These effects are probably related, as it has been proposed that the ROC and COR domains may interact with each other.…”
Section: Pathogenic Mutations In Pd Affect Protein Functionmentioning
confidence: 96%
“…The I2020T mutation has been reported to increase kinase activity [44,57] but also to reduce kinase activity [55]. Data on kinase alterations by mutation at position R1441 are conflicting, with reports of no change [20,55,58] and increased [47,57,59] for R1441C; and unaltered [55] and increased [57] for R1441G. Finally, the Y1699C mutation is reported as unaltered [20,55] and increased [57].…”
Section: Kinase Activity Of Lrrk2mentioning
confidence: 99%
“…Ras-GTPases act as molecular switches that cycle between GTP-bound (active) and GDPbound (inactive) conformations, a process that regulates many diverse cell signaling functions. This process is additionally facilitated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) [59 ].…”
Section: Gtp Binding and Gtpase Activitymentioning
confidence: 99%
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