The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization
Open accessAbstract
LRRK2 (leucine-rich repeat protein kinase 2) is mutated in a significant number of Parkinson's disease patients, but still little is understood about how it is regulated or functions. In the present study we have demonstrated that 14-3-3 protein isoforms interact with LRRK2. Consistent with this, endogenous LRRK2 isolated from Swiss 3T3 cells or various mouse tissues is associated with endogenous 14-3-3 isoforms. We have established that 14-3-3 binding is mediated by phosphorylation of LRRK2 at two conserved residues (Ser910 and Ser935) located before the leucine-rich repeat domain. Our results suggests that mutation of Ser910 and/or Ser935 to disrupt 14-3-3 binding does not affect intrinsic protein kinase activity, but induces LRRK2 to accumulate within discrete cytoplasmic pools, perhaps resembling inclusion bodies. To investigate links between 14-3-3 binding and Parkinson's disease, we studied how 41 reported mutations of LRRK2 affected 14-3-3 binding and cellular localization. Strikingly, we found that five of the six most common pathogenic mutations (R1441C, R1441G, R1441H, Y1699C and I2020T) display markedly reduced phosphorylation of Ser910/Ser935 thereby disrupting interaction with 14-3-3. We have also demonstrated that Ser910/Ser935 phosphorylation and 14-3-3 binding to endogenous LRRK2 is significantly reduced in tissues of homozygous LRRK2(R1441C) knock-in mice. Consistent with 14-3-3 regulating localization, all of the common pathogenic mutations displaying reduced 14-3-3-binding accumulated within inclusion bodies. We also found that three of the 41 LRRK2 mutations analysed displayed elevated protein kinase activity (R1728H, ~2-fold; G2019S, ~3-fold; and T2031S, ~4-fold). These results provide the first evidence suggesting that 14-3-3 regulates LRRK2 and that disruption of the interaction of LRRK2 with 14-3-3 may be linked to Parkinson's disease.
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Cites
Cox, J., & Mann, M. (2008) · Nature Biotechnology · doi:10.1038/nbt.1511 · Cited by 14,855
Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology
Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.11.005 · Cited by 3,005
Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease
Paisán-Ruı́z, C., Jain, S., Evans, E. W., Gilks, W. P., Simón, J., van der Brug, M., de Munain, A. L., Aparicio, S., Gil, A. M., Khan, N., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.10.023 · Cited by 2,405
The Structural Basis for 14-3-3:Phosphopeptide Binding Specificity
Yaffe, M. B., Rittinger, K., Volinia, S., Caron, P. R., Aitken, A., Leffers, H., Gamblin, S. J., Smerdon, S. J., & Cantley, L. C. (1997) · Cell · doi:10.1016/s0092-8674(00)80487-0 · Cited by 1,604
Healy, D. G., Falchi, M., O'Sullivan, S. S., Bonifati, V., Durr, A., Bressman, S., Brice, A., Aasly, J., Zabetian, C. P., Goldwurm, S., et al. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70117-0 · Cited by 1,425
Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity
West, A. B., Moore, D. J., Biskup, S., Bugayenko, A., Smith, W. W., Ross, C. A., Dawson, V. L., & Dawson, T. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507360102 · Cited by 1,228
Physiological and Biochemical Aspects of Nervous Integration
Carlson, F. D. (1968) · Cited by 749
Kinase activity is required for the toxic effects of mutant LRRK2/dardarin
Greggio, E., Jain, S., Kingsbury, A., Bandopadhyay, R., Lewis, P., Kaganovich, A., van der Brug, M. P., Beilina, A., Blackinton, J., Thomas, K. J., et al. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.04.001 · Cited by 671
14-3-3 proteins in the nervous system
Berg, D., Holzmann, C., & Riess, O. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1197 · Cited by 616
α-Synuclein Shares Physical and Functional Homology with 14-3-3 Proteins
Ostrerova, N., Petrucelli, L., Farrer, M., Mehta, N., Choi, P., Hardy, J., & Wolozin, B. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-14-05782.1999 · Cited by 564
Cited by
Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases
Steger, M., Tonelli, F., Ito, G., Davies, P., Trost, M., Vetter, M., Wachter, S., Lorentzen, E., Duddy, G., Wilson, S., et al. (2016) · eLife · doi:10.7554/elife.12813 · Cited by 1,042
Self-citationSteger, M., Diez, F., Dhekne, H. S., Lis, P., Nirujogi, R. S., Karayel, O., Tonelli, F., Martinez, T. N., Lorentzen, E., Pfeffer, S. R., et al. (2017) · eLife · doi:10.7554/elife.31012 · Cited by 482
Self-citationGenetics in Parkinson disease: Mendelian versus non‐Mendelian inheritance
Hernandez, D. G., Reed, X., & Singleton, A. B. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13593 · Cited by 448
“The flanking ankryn, leucine rich repeat andWD40 domains allow for interaction with numerous other proteins including 14-3-3, BAG5, GAK, and Rab7l1 (Nichols et al. 2010; MacLeod et al. 2013; Beilina et al. 2014).”
BackgroundKinase Drug Discovery – What’s Next in the Field?
Cohen, P., & Alessi, D. R. (2013) · ACS Chemical Biology · doi:10.1021/cb300610s · Cited by 377
Self-citationBeilina, A., Rudenko, I. N., Kaganovich, A., Civiero, L., Chau, H., Kalia, S. K., Kalia, L. V., Lobbestael, E., Chia, R., Ndukwe, K., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1318306111 · Cited by 348
Metadata
- Authors
- Nichols, R. J., Dzamko, N., Morrice, N. A., Campbell, D. G., Deak, M., Ordureau, A., Macartney, T., Tong, Y., Shen, J., Prescott, A. R., & Alessi, D. R.
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2010-08-27
- Volume
- 430
- Issue
- 3
- Pages
- 393-404
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W1977391806
- Cited by
- 386
- References
- 32
- FWCI
- 12.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Nichols, R. J., Dzamko, N., Morrice, N. A., Campbell, D. G., Deak, M., Ordureau, A., Macartney, T., Tong, Y., Shen, J., Prescott, A. R., & Alessi, D. R. (2010). 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochemical Journal. https://doi.org/10.1042/bj20100483
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