| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of Parkinson's disease (PD). LRRK2 contains a Ras of complex proteins (ROC) domain that may act as a GTPase to regulate its protein kinase activity. The structure of ROC and the mechanism(s) by which it regulates kinase activity are not known. Here, we report the crystal structure of the LRRK2 ROC domain in complex with GDP-Mg(2+) at 2.0-A resolution. The structure displays a dimeric fold generated by extensive domain-swapping, resulting in a pair of active sites constructed with essential functional groups contributed from both monomers. Two PD-associated pathogenic residues, R1441 and I1371, are located at the interface of two monomers and provide exquisite interactions to stabilize the ROC dimer. The structure demonstrates that loss of stabilizing forces in the ROC dimer is likely related to decreased GTPase activity resulting from mutations at these sites. Our data suggest that the ROC domain may regulate LRRK2 kinase activity as a dimer, possibly via the C-terminal of ROC (COR) domain as a molecular hinge. The structure of the LRRK2 ROC domain also represents a signature from a previously undescribed class of GTPases from complex proteins and results may provide a unique molecular target for therapeutics in PD.
Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase.,Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, Cookson MR Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1499-504. Epub 2008 Jan 29. PMID:18230735[39]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16842-7. Epub 2005 Nov 3. PMID:16269541 doi:10.1073/pnas.0507360102
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- ↑ Goldwurm S, Di Fonzo A, Simons EJ, Rohe CF, Zini M, Canesi M, Tesei S, Zecchinelli A, Antonini A, Mariani C, Meucci N, Sacilotto G, Sironi F, Salani G, Ferreira J, Chien HF, Fabrizio E, Vanacore N, Dalla Libera A, Stocchi F, Diroma C, Lamberti P, Sampaio C, Meco G, Barbosa E, Bertoli-Avella AM, Breedveld GJ, Oostra BA, Pezzoli G, Bonifati V. The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor. J Med Genet. 2005 Nov;42(11):e65. PMID:16272257 doi:42/11/e65
- ↑ Nichols WC, Pankratz N, Hernandez D, Paisan-Ruiz C, Jain S, Halter CA, Michaels VE, Reed T, Rudolph A, Shults CW, Singleton A, Foroud T. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet. 2005 Jan 29-Feb 4;365(9457):410-2. PMID:15680455 doi:S0140-6736(05)17828-3
- ↑ Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, Goldwurm S, Breedveld G, Sampaio C, Meco G, Barbosa E, Oostra BA, Bonifati V. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet. 2005 Jan 29-Feb 4;365(9457):412-5. PMID:15680456 doi:S0140-6736(05)17829-5
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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
- ↑ Paisan-Ruiz C, Lang AE, Kawarai T, Sato C, Salehi-Rad S, Fisman GK, Al-Khairallah T, St George-Hyslop P, Singleton A, Rogaeva E. LRRK2 gene in Parkinson disease: mutation analysis and case control association study. Neurology. 2005 Sep 13;65(5):696-700. PMID:16157901 doi:65/5/696
- ↑ Skipper L, Shen H, Chua E, Bonnard C, Kolatkar P, Tan LC, Jamora RD, Puvan K, Puong KY, Zhao Y, Pavanni R, Wong MC, Yuen Y, Farrer M, Liu JJ, Tan EK. Analysis of LRRK2 functional domains in nondominant Parkinson disease. Neurology. 2005 Oct 25;65(8):1319-21. PMID:16247070 doi:65/8/1319
- ↑ 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
- ↑ Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, Cookson MR. Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1499-504. Epub 2008 Jan 29. PMID:18230735
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