| 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
[1433S_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression. [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
Binding of 14-3-3 proteins to LRRK2 is known to be impaired by a number of Parkinson's disease (PD)-relevant mutations. Abrogation of this interaction is connected to enhanced LRRK2 kinase activity which in turn is implicated in increased ubiquitination of LRRK2, accumulation of LRRK2 into inclusion bodies and reduction of neurite length. Hence, the interaction between 14-3-3 and LRRK2 is of significant interest as a possible drug target for the treatment of PD. However, LRRK2 possesses multiple sites that upon phosphorylation can bind to 14-3-3, thus rendering the interaction relatively complex. Using biochemical assays and crystal structures, we characterize the multivalent interaction between these two proteins.
Structural interface between LRRK2 and 14-3-3 protein.,Stevers L, de Vries R, Doveston R, Milroy LG, Brunsveld L, Ottmann C Biochem J. 2017 Feb 15. pii: BCJ20161078. doi: 10.1042/BCJ20161078. PMID:28202711[39]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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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
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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
- ↑ 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
- ↑ Stevers L, de Vries R, Doveston R, Milroy LG, Brunsveld L, Ottmann C. Structural interface between LRRK2 and 14-3-3 protein. Biochem J. 2017 Feb 15. pii: BCJ20161078. doi: 10.1042/BCJ20161078. PMID:28202711 doi:http://dx.doi.org/10.1042/BCJ20161078
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