Browse > Article
http://dx.doi.org/10.5352/JLS.2018.28.2.170

Methionyl-tRNA-synthetase is a Novel Interacting Protein of LRRK2  

Kim, Hyejung (InAm Neuroscience Research Center, Wonkwang University)
Ho, Dong Hwan (InAm Neuroscience Research Center, Wonkwang University)
Son, Ilhong (InAm Neuroscience Research Center, Wonkwang University)
Seol, Wongi (InAm Neuroscience Research Center, Wonkwang University)
Publication Information
Journal of Life Science / v.28, no.2, 2018 , pp. 170-175 More about this Journal
Abstract
Parkinson's disease (PD) is the most common movement disorder and the second most common neurodegenerative disease after Alzheimer's disease. Approximately 5~10% of PD patients are familial PD cases. Leucine-rich repeat kinase 2 (LRRK2) has been known to be a causal gene of PD when it is mutated. LRRK2 contains the functional kinase and GTPase domains as well as leucine-rich repeat (LRR) and WD40 domains that are known to play critical roles for protein-protein interaction, suggesting that LRRK2-interacting proteins are important regulators for PD pathogenesis. In an effort to identify proteins interacting with LRRK2, we carried out co-immunoprecipitation of LRRK2 antibody using extracts of NIH3T3 cells that express LRRK2 at a relatively high level. The mass spectrometry analysis of a precipitated band revealed that the co-precipitated band was methionyl-tRNA synthetase (MRS), an ancient enzyme that transfers methionin to its cognate tRNA. The interaction of MRS with LRRK2 was confirmed again by co-immunoprecipitation of endogenous proteins and GST pull-down assays. However, LRRK2 did not phosphorylate recombinant MRS protein in in vitro kinase assays, and over-expression of LRRK2 or MRS did not affect the stability of its partner protein. Our data indicate that LRRK2 interacts with but does not phosphorylate MRS, and the stability of each partner is not affected by the other.
Keywords
Kinase; LRRK2; methionyl-tRNA synthetase; Parkinson's disease; protein-protein interaction;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Greggio, E. and Cookson, M. R. 2009. Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN Neuro. 1, e00002.
2 Guerreiro, P. S., Gerhardt, E., Lopes da Fonseca, T., Bahr, M., Outeiro, T. F. and Eckermann, K. 2015. LRRK2 promotes tau accumulation, aggregation and release. Mol. Neurobiol. 53, 3124-3135.
3 Guerreiro, P. S., Huang, Y., Gysbers, A., Cheng, D. and Gai, W. P., et al. 2013. LRRK2 interactions with alpha-synuclein in Parkinson's disease brains and in cell models. J. Mol. Med. (Berl) 91, 513-522.   DOI
4 Hardie, D. G. 1990. Roles of protein kinases and phosphatases in signal transduction. Symp. Soc. Exp. Biol. 44, 241-255.
5 Hatcher, J. M., Choi, H. G., Alessi, D. R. and Gray, N. S. 2017. Small-Molecule Inhibitors of LRRK2. Adv. Neurobiol. 14, 241-264.
6 Ho, D. H., Kim, H., Kim, J., Sim, H. and Ahn, H., et al. 2015. Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21(WAF1/CIP1) expression. Mol. Brain 8, 54.   DOI
7 Hwang, O. 2013. Role of oxidative stress in Parkinson's disease. Exp. Neurobiol. 22, 11-17.   DOI
8 Kachergus, J., Mata, I. F., Hulihan, M., Taylor, J. P. and Lincoln, S., et al. 2005. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am. J. Hum. Genet. 76, 672-680.   DOI
9 Kuwahara, T., Inoue, K., D'Agati, V. D., Fujimoto, T. and Eguchi, T., et al. 2016. LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts. Sci. Rep. 6, 29945.   DOI
10 Kwon, N. H., Kang, T., Lee, J. Y., Kim, H. H. and Kim, H. R., et al. 2011. Dual role of methionyl-tRNA synthetase in the regulation of translation and tumor suppressor activity of aminoacyl-tRNA synthetase-interacting multifunctional protein-3. Proc. Natl. Acad. Sci. USA. 108, 19635-19640.   DOI
11 Manzoni, C. and Lewis, P. A. 2017. LRRK2 and autophagy. Adv. Neurobiol. 14, 89-105.
12 Belin, A. C. and Westerlund, M. 2008. Parkinson's disease: a genetic perspective. Febs. J. 275, 1377-1383.   DOI
13 Factor, S. A. 2001. Parkinson's Disease: initial treatment with levodopa or dopamine agonists. Curr. Treat. Options Neurol. 3, 479-493.   DOI
14 Martin, I., Dawson, V. L. and Dawson, T. M. 2011. Recent advances in the genetics of Parkinson's disease. Annu. Rev. Genomics Hum. Genet. 12, 301-325.   DOI
15 Martin, I., Kim, J. W., Lee, B. D., Kang, H. C. and Xu, J. C., et al. 2014. Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 157, 472-485.   DOI
16 Monfrini, E. and Di Fonzo, A. 2017. Leucine-rich repeat kinase (LRRK2) genetics and Parkinson'sdisease. Adv. Neurobiol. 14, 3-30.
17 Paisan-Ruiz, C., Jain S., Evans, E. W., Gilks, W. P. and Simon, J., et al. 2004. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595-600.   DOI
18 Seol, W. 2010. Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease. BMB Rep. 43, 233-244.   DOI
19 Seol, W., Mahon, M. J., Lee, Y. K. and Moore, D. D. 1996. Two receptor interacting domains in the nuclear hormone receptor corepressor RIP13/N-CoR. Mol. Endocrinol. 10, 1646-1655.
20 Shin, N., Jeong, H., Kwon, J., Heo, H. Y. and Kwon, J. J., et al. 2008. LRRK2 regulates synaptic vesicle endocytosis. Exp. Cell Res. 314, 2055-2065   DOI
21 Tanner, C. M. and Goldman, S. M. 1996. Epidemiology of Parkinson's disease. Neurol. Clin. 14, 317-335.   DOI
22 Woese, C. R., Olsen, G. J., Ibba, M. and Soll, D. 2000. Aminoacyl-tRNA synthetases, the genetic code, and the evolutionary process. Microbiol. Mol. Biol. Rev. 64, 202-236.   DOI
23 Yun, H. J., Kim, H., Ga, I., Oh, H. and Ho, D. H., et al. 2015. An early endosome regulator, Rab5b, is an LRRK2 kinase substrate. J. Biochem. 157, 485-495.   DOI
24 Yun, H. J., Park, J., Ho, D. H., Kim, H. and Kim, C. H., et al. 2013. LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25. Exp. Mol. Med. 45, e36   DOI
25 Zimprich, A., Biskup, S., Leitner, P., Lichtner, P. and Farrer, M., et al. 2004. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601-607.   DOI