| 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
Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD) and a risk factor for the sporadic form. Increased kinase activity was shown in patients with both familial and sporadic PD, making LRRK2 kinase inhibitors a major focus of drug development efforts. Although much progress has been made in understanding the structural biology of LRRK2, there are no available structures of LRRK2 inhibitor complexes. To this end, we solved cryo-electron microscopy structures of LRRK2, wild-type and PD-linked mutants, bound to the LRRK2-specific type I inhibitor MLi-2 and the broad-spectrum type II inhibitor GZD-824. Our structures revealed an active-like LRRK2 kinase in the type I inhibitor complex, and an inactive DYG-out in the type II inhibitor complex. Our structural analysis also showed how inhibitor-induced conformational changes in LRRK2 are affected by its autoinhibitory N-terminal repeats. The structures provide a template for the rational development of LRRK2 kinase inhibitors covering both canonical inhibitor binding modes.
Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures.,Sanz Murillo M, Villagran Suarez A, Dederer V, Chatterjee D, Alegrio Louro J, Knapp S, Mathea S, Leschziner AE Sci Adv. 2023 Dec;9(48):eadk6191. doi: 10.1126/sciadv.adk6191. Epub 2023 Dec 1. PMID:38039358[39]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ 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
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- ↑ 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
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- ↑ 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
- ↑ Sanz Murillo M, Villagran Suarez A, Dederer V, Chatterjee D, Alegrio Louro J, Knapp S, Mathea S, Leschziner AE. Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures. Sci Adv. 2023 Dec;9(48):eadk6191. PMID:38039358 doi:10.1126/sciadv.adk6191
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