| Structural highlights
Disease
[LRRK2_HUMAN] Defects in LRRK2 are the cause of Parkinson disease type 8 (PARK8) [MIM:607060]. A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]
Function
[LRRK2_HUMAN] May play a role in the phosphorylation of proteins central to Parkinson disease. Phosphorylates PRDX3. May also have GTPase activity. Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes.[35] [36] [37] [38]
Publication Abstract from PubMed
Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson's disease (PD)(1) and is also linked to its idiopathic form(2). LRRK2 is proposed to function in membrane trafficking(3) and co-localizes with microtubules(4). Despite LRRK2's fundamental importance for understanding and treating PD, there is limited structural information on it. Here we report the 3.5A structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported 14A cryo-electron tomography in situ structure(5). We propose that the conformation of LRRK2's kinase domain regulates its microtubule interaction, with a closed conformation favouring oligomerization on microtubules. We show that the catalytic half of LRRK2 is sufficient for filament formation and blocks the motility of the microtubule-based motors kinesin-1 and cytoplasmic dynein-1 in vitro. Kinase inhibitors that stabilize an open conformation relieve this interference and reduce LRRK2 filament formation in cells, while those that stabilize a closed conformation do not. Our findings suggest that LRRK2 can act as a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.
Structure of LRRK2 in Parkinson's disease and model for microtubule interaction.,Deniston CK, Salogiannis J, Mathea S, Snead DM, Lahiri I, Matyszewski M, Donosa O, Watanabe R, Bohning J, Shiau AK, Knapp S, Villa E, Reck-Peterson SL, Leschziner AE Nature. 2020 Aug 19. pii: 10.1038/s41586-020-2673-2. doi:, 10.1038/s41586-020-2673-2. PMID:32814344[39]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Toft M, Mata IF, Kachergus JM, Ross OA, Farrer MJ. LRRK2 mutations and Parkinsonism. Lancet. 2005 Apr 2-8;365(9466):1229-30. PMID:15811454 doi:10.1016/S0140-6736(05)74809-1
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- ↑ Mata IF, Kachergus JM, Taylor JP, Lincoln S, Aasly J, Lynch T, Hulihan MM, Cobb SA, Wu RM, Lu CS, Lahoz C, Wszolek ZK, Farrer MJ. Lrrk2 pathogenic substitutions in Parkinson's disease. Neurogenetics. 2005 Dec;6(4):171-7. Epub 2005 Sep 17. PMID:16172858 doi:10.1007/s10048-005-0005-1
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- ↑ Farrer M, Stone J, Mata IF, Lincoln S, Kachergus J, Hulihan M, Strain KJ, Maraganore DM. LRRK2 mutations in Parkinson disease. Neurology. 2005 Sep 13;65(5):738-40. PMID:16157908 doi:65/5/738
- ↑ Zabetian CP, Samii A, Mosley AD, Roberts JW, Leis BC, Yearout D, Raskind WH, Griffith A. A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations. Neurology. 2005 Sep 13;65(5):741-4. PMID:16157909 doi:10.1212/01.wnl.0000172630.22804.73
- ↑ Mata IF, Taylor JP, Kachergus J, Hulihan M, Huerta C, Lahoz C, Blazquez M, Guisasola LM, Salvador C, Ribacoba R, Martinez C, Farrer M, Alvarez V. LRRK2 R1441G in Spanish patients with Parkinson's disease. Neurosci Lett. 2005 Jul 15;382(3):309-11. Epub 2005 Apr 13. PMID:15925109 doi:10.1016/j.neulet.2005.03.033
- ↑ Infante J, Rodriguez E, Combarros O, Mateo I, Fontalba A, Pascual J, Oterino A, Polo JM, Leno C, Berciano J. LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease. Neurosci Lett. 2006 Mar 13;395(3):224-6. Epub 2005 Nov 18. PMID:16298482 doi:10.1016/j.neulet.2005.10.083
- ↑ Gosal D, Ross OA, Wiley J, Irvine GB, Johnston JA, Toft M, Mata IF, Kachergus J, Hulihan M, Taylor JP, Lincoln SJ, Farrer MJ, Lynch T, Mark Gibson J. Clinical traits of LRRK2-associated Parkinson's disease in Ireland: a link between familial and idiopathic PD. Parkinsonism Relat Disord. 2005 Sep;11(6):349-52. PMID:16102999 doi:S1353-8020(05)00091-X
- ↑ Gaig C, Ezquerra M, Marti MJ, Munoz E, Valldeoriola F, Tolosa E. LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance. Arch Neurol. 2006 Mar;63(3):377-82. PMID:16533964 doi:63/3/377
- ↑ Tan EK, Zhao Y, Skipper L, Tan MG, Di Fonzo A, Sun L, Fook-Chong S, Tang S, Chua E, Yuen Y, Tan L, Pavanni R, Wong MC, Kolatkar P, Lu CS, Bonifati V, Liu JJ. The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Hum Genet. 2007 Feb;120(6):857-63. Epub 2006 Sep 30. PMID:17019612 doi:10.1007/s00439-006-0268-0
- ↑ Paisan-Ruiz C, Nath P, Washecka N, Gibbs JR, Singleton AB. Comprehensive analysis of LRRK2 in publicly available Parkinson's disease cases and neurologically normal controls. Hum Mutat. 2008 Apr;29(4):485-90. doi: 10.1002/humu.20668. PMID:18213618 doi:10.1002/humu.20668
- ↑ Bardien S, Lesage S, Brice A, Carr J. Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson's disease. Parkinsonism Relat Disord. 2011 Aug;17(7):501-8. doi:, 10.1016/j.parkreldis.2010.11.008. PMID:21641266 doi:10.1016/j.parkreldis.2010.11.008
- ↑ Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18676-81. Epub 2005 Dec 13. PMID:16352719 doi:10.1073/pnas.0508052102
- ↑ Zach S, Felk S, Gillardon F. Signal transduction protein array analysis links LRRK2 to Ste20 kinases and PKC zeta that modulate neuronal plasticity. PLoS One. 2010 Oct 7;5(10):e13191. doi: 10.1371/journal.pone.0013191. PMID:20949042 doi:10.1371/journal.pone.0013191
- ↑ Angeles DC, Gan BH, Onstead L, Zhao Y, Lim KL, Dachsel J, Melrose H, Farrer M, Wszolek ZK, Dickson DW, Tan EK. Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. Hum Mutat. 2011 Dec;32(12):1390-7. doi: 10.1002/humu.21582. Epub 2011 Sep 12. PMID:21850687 doi:10.1002/humu.21582
- ↑ Gomez-Suaga P, Luzon-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, Woodman PG, Churchill GC, Hilfiker S. Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet. 2012 Feb 1;21(3):511-25. doi: 10.1093/hmg/ddr481. Epub 2011 Oct, 19. PMID:22012985 doi:10.1093/hmg/ddr481
- ↑ Deniston CK, Salogiannis J, Mathea S, Snead DM, Lahiri I, Matyszewski M, Donosa O, Watanabe R, Bohning J, Shiau AK, Knapp S, Villa E, Reck-Peterson SL, Leschziner AE. Structure of LRRK2 in Parkinson's disease and model for microtubule interaction. Nature. 2020 Aug 19. pii: 10.1038/s41586-020-2673-2. doi:, 10.1038/s41586-020-2673-2. PMID:32814344 doi:https://dx.doi.org/10.1038/s41586-020-2673-2
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