The role of (auto)-phosphorylation in the complex activation mechanism of LRRK2
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Panagiotis S. Athanasopoulos
Panagiotis S. Athanasopoulos studied Biochemistry and Biotechnology at the University of Thessaly, Greece, in a Diploma program. Then he moved to Utrecht, the Netherlands, for his Master’s degree in Biomolecular Sciences. After that he pursued his PhD in the lab of Prof Dr. Rolf Heumann, in Ruhr University Bochum, Germany. His PhD studies were focused on hereditary Parkinson’s disease (PD). Currently he his working in the lab of Dr. Arjan Kortholt, where he continues to work as a postdoctoral fellow on the same project as his PhD topic.
Rolf Heumann joined the Max-Planck-Institute for Biochemistry/Martinsried to perform his diploma/PhD thesis projects in the field of cellular neuroscience after studying Microbiology at the Technical University of Munich and the Queen Elizabeth College in London. In 1979, he continued as a research assistant at the Max-Planck-Institute for Psychiatry in Martinsried exploring molecular mechanisms of neuronal regeneration and advancing the field of intracellular signaling mechanisms of neurotrophic factors in the brain. In 1991, he was appointed to the Chair holder of the Department of Biochemistry-Molecular Neurobiochemistry in the Faculty for Chemistry and Biochemistry at the Ruhr-University of Bochum. In 2012 he retired from the Department Chair and was appointed as a Senior Professor at the Ruhr-University being responsible for the FET-open Horizon 2020 project MAGNEURON, where he has worked to date.
Arjan Kortholt studied Chemistry and received his PhD degree from the University of Groningen in 2009. In 2007 he started working on the biochemical and structural characterization of small G-proteins in the laboratory of Dr. Wittinghofer (MPI Dortmund). Since 2010 he has been working at the University of Groningen, where he holds a position as Associate Professor. The primary aim of his current research is therapeutic targeting of LRRK2-mediated Parkinson’s disease by elucidating the structure, activation mechanism and function of LRRK2 and related Roco family proteins.
Abstract
Mutations in human leucine-rich-repeat kinase 2 (LRRK2) have been found to be the most frequent cause of late-onset Parkinson’s Disease (PD). LRRK2 is a large protein with two enzymatic domains, a GTPase and a kinase domain. A cluster of (auto)-phosphorylation sites within the N-terminus of LRRK2 have been shown to be crucial for the localization of LRRK2 and is important for PD pathogenesis. In addition, phosphorylation of sites within the G-domain of the protein affect GTPase activity. Here we discuss the role of these (auto)-phosphorylation sites of LRRK2 and their regulation by phosphatases and upstream kinases.
About the authors
Panagiotis S. Athanasopoulos studied Biochemistry and Biotechnology at the University of Thessaly, Greece, in a Diploma program. Then he moved to Utrecht, the Netherlands, for his Master’s degree in Biomolecular Sciences. After that he pursued his PhD in the lab of Prof Dr. Rolf Heumann, in Ruhr University Bochum, Germany. His PhD studies were focused on hereditary Parkinson’s disease (PD). Currently he his working in the lab of Dr. Arjan Kortholt, where he continues to work as a postdoctoral fellow on the same project as his PhD topic.
Rolf Heumann joined the Max-Planck-Institute for Biochemistry/Martinsried to perform his diploma/PhD thesis projects in the field of cellular neuroscience after studying Microbiology at the Technical University of Munich and the Queen Elizabeth College in London. In 1979, he continued as a research assistant at the Max-Planck-Institute for Psychiatry in Martinsried exploring molecular mechanisms of neuronal regeneration and advancing the field of intracellular signaling mechanisms of neurotrophic factors in the brain. In 1991, he was appointed to the Chair holder of the Department of Biochemistry-Molecular Neurobiochemistry in the Faculty for Chemistry and Biochemistry at the Ruhr-University of Bochum. In 2012 he retired from the Department Chair and was appointed as a Senior Professor at the Ruhr-University being responsible for the FET-open Horizon 2020 project MAGNEURON, where he has worked to date.
Arjan Kortholt studied Chemistry and received his PhD degree from the University of Groningen in 2009. In 2007 he started working on the biochemical and structural characterization of small G-proteins in the laboratory of Dr. Wittinghofer (MPI Dortmund). Since 2010 he has been working at the University of Groningen, where he holds a position as Associate Professor. The primary aim of his current research is therapeutic targeting of LRRK2-mediated Parkinson’s disease by elucidating the structure, activation mechanism and function of LRRK2 and related Roco family proteins.
Acknowledgments
We have received funding from the Michael J. Fox Foundation for Parkinson’s Research. RH was funded by HORIZON 2020, Nr 686841.
References
Alcalay, R.N., Mirelman, A., Saunders-Pullman, R., Tang, M.-X., Mejia Santana, H., Raymond, D., Roos, E., Orbe-Reilly, M., Gurevich, T., Bar Shira, A., et al. (2013). Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations. Mov. Disord. 28, 1966–1971.10.1002/mds.25647Suche in Google Scholar PubMed PubMed Central
Anand, V.S., Reichling, L.J., Lipinski, K., Stochaj, W., Duan, W., Kelleher, K., Pungaliya, P., Brown, E.L., Reinhart, P.H., Somberg, R., et al. (2009). Investigation of leucine-rich repeat kinase 2: enzymological properties and novel assays. FEBS J. 276, 466–478.10.1111/j.1742-4658.2008.06789.xSuche in Google Scholar PubMed
Athanasopoulos, P.S., Wright, J., Neumann, S., Kutsch, M., Wolters, D., Tan, E.K., Bichler, Z., Herrmann, C., and Heumann, R. (2016). Identification of protein phosphatase 2A as an interacting protein of leucine-rich repeat kinase 2. Biol. Chem. 397, 541–554.10.1515/hsz-2015-0189Suche in Google Scholar PubMed
Carrion, M.D.P., Marsicano, S., Daniele, F., Marte, A., Pischedda, F., Di Cairano, E., Piovesana, E., von Zweydorf, F., Kremmer, E., Gloeckner, C.J., et al. (2017). The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions. Sci. Rep. 7, 5377.10.1038/s41598-017-05760-9Suche in Google Scholar PubMed PubMed Central
Cookson, M. and Bandmann, O. (2010). Parkinson’s disease: insights from pathways. Hum. Mol. Genet. 19, R21–R27.10.1093/hmg/ddq167Suche in Google Scholar PubMed PubMed Central
Doggett, E.A., Zhao, J., Mork, C.N., Hu, D., and Nichols, R.J. (2012). Phosphorylation of LRRK2 serines 955 and 973 is disrupted by Parkinson’s disease mutations and LRRK2 pharmacological inhibition. J. Neurochem. 120, 37–45.10.1111/j.1471-4159.2011.07537.xSuche in Google Scholar PubMed
Dzamko, N., Deak, M., Hentati, F., Reith, A.D., Prescott, A.R., Alessi, D.R., and Nichols, R.J. (2010). Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem. J. 430, 405–413.10.1042/BJ20100784Suche in Google Scholar PubMed PubMed Central
Gasser, T., Hardy, J., and Mizuno, Y. (2011). Milestones in PD genetics. Mov. Disord. 26, 1042–1048.10.1002/mds.23637Suche in Google Scholar PubMed
Greggio, E. and Cookson, M.R. (2009). Leucine-rich repeat kinase 2 mutations and Parkinson’s disease: three questions. ASN Neuro 1, 13–24.10.1042/AN20090007Suche in Google Scholar PubMed PubMed Central
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). Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol. Dis. 23, 329–341.10.1016/j.nbd.2006.04.001Suche in Google Scholar PubMed
Greggio, E., Taymans, J.M., Zhen, E.Y., Ryder, J., Vancraenenbroeck, R., Beilina, A., Sun, P., Deng, J., Jaffe, H., Baekelandt, V., et al. (2009). The Parkinson’s disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites. Biochem. Biophys. Res. Commun. 389, 449–454.10.1016/j.bbrc.2009.08.163Suche in Google Scholar
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). Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol. 7, 583–590.10.1016/S1474-4422(08)70117-0Suche in Google Scholar
Islam, M.S., Nolte, H., Jacob, W., Ziegler, A.B., Pütz, S., Grosjean, Y., Szczepanowska, K., Trifunovic, A., Braun, T., Heumann, H., et al. (2016). Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson’s disease. Hum. Mol. Genet. 25, 5365–5382.Suche in Google Scholar
Jaleel, M., Nichols, R.J., Deak, M., Campbell, D.G., Gillardon, F., Knebel, A., and Alessi, D.R. (2007). LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson’s disease mutants affect kinase activity. Biochem. J. 405, 307–317.10.1042/BJ20070209Suche in Google Scholar
Lavalley, N.J., Slone, S.R., Ding, H., West, A.B., and Yacoubian, T.A. (2016). 14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening. Hum. Mol. Genet. 25, 109–122.10.1093/hmg/ddv453Suche in Google Scholar
Lees, A.J., Hardy, J., and Revesz, T. (2009). Parkinson’s disease. Lancet 373, 2055–2066.10.1016/S0140-6736(09)60492-XSuche in Google Scholar
Lesage, S., Janin, S., Lohmann, E., Leutenegger, A.-L., Leclere, L., Viallet, F., Pollak, P., Durif, F., Thobois, S., Layet, V., et al. (2007). LRRK2emph exon 41 mutations in sporadic Parkinson disease in Europeans. Arch. Neurol. 64, 425.10.1001/archneur.64.3.425Suche in Google Scholar PubMed
Lobbestael, E., Zhao, J., Rudenko, I.N.N., Beylina, A., Gao, F., Wetter, J., Beullens, M., Bollen, M., Cookson, M.R.R., Baekelandt, V., et al. (2013). Identification of protein phosphatase 1 as a regulator of the LRRK2 phosphorylation cycle. Biochem. J. 456, 119–128.10.1042/BJ20121772Suche in Google Scholar PubMed PubMed Central
Muda, K., Bertinetti, D., Gesellchen, F., Hermann, J.S., von Zweydorf, F., Geerlof, A., Jacob, A., Ueffing, M., Gloeckner, C.J., and Herberg, F.W. (2014). Parkinson-related LRRK2 mutation R1441C/G/H impairs PKA phosphorylation of LRRK2 and disrupts its interaction with 14-3-3. Proc. Natl. Acad. Sci. USA 111, E34–E43.10.1073/pnas.1312701111Suche in Google Scholar PubMed PubMed Central
Nichols, R., Dzamko, N., Morrice, N., and Campbell, D. (2010). 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson’s disease-associated mutations and regulates cytoplasmic localization. Biochem. J 430, 393–404.10.1042/BJ20100483Suche in Google Scholar PubMed PubMed Central
Pan, P.-Y., Li, X., Wang, J., Powell, J., Wang, Q., Zhang, Y., Chen, Z., Wicinski, B., Hof, P., Ryan, T.A., et al. (2017). Parkinson’s disease-associated LRRK2 hyperactive kinase mutant disrupts synaptic vesicle trafficking in ventral midbrain neurons. J. Neurosci. 37, 11366–11376.10.1523/JNEUROSCI.0964-17.2017Suche in Google Scholar PubMed PubMed Central
Ramírez, M.B., Ordóñez, A.J.L., Fdez, E., Madero-Pérez, J., Gonnelli, A., Drouyer, M., Chartier-Harlin, M.-C., Taymans, J.-M., Bubacco, L., Greggio, E., et al. (2017). GTP binding regulates cellular localization of Parkinson’s disease-associated LRRK2. Hum. Mol. Genet. 26, 2747–2767.10.1093/hmg/ddx161Suche in Google Scholar PubMed PubMed Central
Steger, M., Tonelli, F., Ito, G., Davies, P., Trost, M., Vetter, M., Wachter, S., Lorentzen, E., Duddy, G., Wilson, S., et al. (2016). Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife 5, 1–28.10.7554/eLife.12813Suche in Google Scholar PubMed PubMed Central
Taymans, J.M., Vancraenenbroeck, R., Ollikainen, P., Beilina, A., Lobbestael, E., de Maeyer, M., Baekelandt, V., and Cookson, M.R. (2011). LRRK2 kinase activity is dependent on LRRK2 gtp binding capacity but independent of LRRK2 GTP binding. PLoS One 6, 1–11.10.1371/journal.pone.0023207Suche in Google Scholar PubMed PubMed Central
Terheyden, S., Nederveen-Schippers, L.M., and Kortholt, A. (2016). The unconventional G-protein cycle of LRRK2 and Roco proteins. Biochem. Soc. Trans. 44, 1611–1616.10.1042/BST20160224Suche in Google Scholar PubMed
Trinh, J., Guella, I., and Farrer, M.J. (2014). Disease penetrance of late-onset parkinsonism: a meta-analysis. J. Am. Med. Assoc. Neurol. 71, 1535–1539.10.1001/jamaneurol.2014.1909Suche in Google Scholar PubMed
Webber, P.J., Smith, A.D., Sen, S., Renfrow, M.B., Mobley, J.A., and West, A.B. (2011). Autophosphorylation in the leucine-rich repeat kinase 2 (LRRK2) GTPase domain modifies kinase and GTP-binding activities. J. Mol. Biol. 412, 94–110.10.1016/j.jmb.2011.07.033Suche in Google Scholar PubMed PubMed Central
West, A.B., Moore, D.J., Biskup, S., Bugayenko, A., Smith, W.W., Ross, C.A., Dawson, V.L., and Dawson, T.M. (2005). Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. USA 102, 16842–16847.10.1073/pnas.0507360102Suche in Google Scholar PubMed PubMed Central
West, A.B., Moore, D.J., Choi, C., Andrabi, S.A., Li, X., Dikeman, D., Biskup, S., Zhang, Z., Lim, K.-L., Dawson, V.L., et al. (2007). Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum. Mol. Genet. 16, 223–232.10.1093/hmg/ddl471Suche in Google Scholar PubMed
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). Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601–607.10.1016/j.neuron.2004.11.005Suche in Google Scholar PubMed
©2018 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Highlight Issue ‘Molecular Basis of Life 2017’
- HIGHLIGHT: GBM Fall Meeting “Molecular Basis of Life 2017”
- Neuronal RNP granules: from physiological to pathological assemblies
- Regulation of LRRK2: insights from structural and biochemical analysis
- The role of (auto)-phosphorylation in the complex activation mechanism of LRRK2
- Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3
- Hypoxia and serum deprivation induces glycan alterations in triple negative breast cancer cells
- Targeting autophagy for the treatment of cancer
- From molecules to patients: exploring the therapeutic role of soluble guanylate cyclase stimulators
- DNA-encoded libraries – an efficient small molecule discovery technology for the biomedical sciences
- Transcytosis of payloads that are non-covalently complexed to bispecific antibodies across the hCMEC/D3 blood-brain barrier model
- Mitochondrial contributions to neuronal development and function
- Intracellular communication between lipid droplets and peroxisomes: the Janus face of PEX19
- Protein crystallization in living cells
- Synthetic DNA filaments: from design to applications
- Spectroscopic characterization of the Co-substituted C-terminal domain of rubredoxin-2
- Twitch or swim: towards the understanding of prokaryotic motion based on the type IV pilus blueprint
Artikel in diesem Heft
- Frontmatter
- Highlight Issue ‘Molecular Basis of Life 2017’
- HIGHLIGHT: GBM Fall Meeting “Molecular Basis of Life 2017”
- Neuronal RNP granules: from physiological to pathological assemblies
- Regulation of LRRK2: insights from structural and biochemical analysis
- The role of (auto)-phosphorylation in the complex activation mechanism of LRRK2
- Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3
- Hypoxia and serum deprivation induces glycan alterations in triple negative breast cancer cells
- Targeting autophagy for the treatment of cancer
- From molecules to patients: exploring the therapeutic role of soluble guanylate cyclase stimulators
- DNA-encoded libraries – an efficient small molecule discovery technology for the biomedical sciences
- Transcytosis of payloads that are non-covalently complexed to bispecific antibodies across the hCMEC/D3 blood-brain barrier model
- Mitochondrial contributions to neuronal development and function
- Intracellular communication between lipid droplets and peroxisomes: the Janus face of PEX19
- Protein crystallization in living cells
- Synthetic DNA filaments: from design to applications
- Spectroscopic characterization of the Co-substituted C-terminal domain of rubredoxin-2
- Twitch or swim: towards the understanding of prokaryotic motion based on the type IV pilus blueprint
