Structural biology of the LRRK2 GTPase and kinase domains: Implications for regulation

Frontiers in Molecular Neuroscience

Volumn 7, Issue MAY, 2014, Pages

  Gilsbach, Bernd K ^a   Kortholt, Arjan ^a  

^a UNIVERSITY OF GRONINGEN   (Netherlands)

Author keywords

G protein; Kinase; LRRK2; Parkinson's disease; Roco; Structure

Indexed keywords

BETA TRANSDUCIN REPEAT CONTAINING PROTEIN; GUANINE NUCLEOTIDE BINDING PROTEIN; GUANOSINE TRIPHOSPHATASE; H1152; LEUCINE RICH REPEAT KINASE 2; PEPTIDES AND PROTEINS; PROTEIN SERINE THREONINE KINASE INHIBITOR; RAS PROTEIN; ROCO PROTEIN; UNCLASSIFIED DRUG;

BINDING AFFINITY; DICTYOSTELIUM DISCOIDEUM; DIMERIZATION; MUTATION; NONHUMAN; PARKINSON DISEASE; PHOSPHORYLATION AND DEPHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; SIGNAL TRANSDUCTION;

EID: 84899889585     PISSN: 16625099     EISSN: None     Source Type: Journal    
DOI: 10.3389/fnmol.2014.00032     Document Type: Review

References (80)

1. Anand, V. S., Reichling, L. J., Lipinski, K., Stochaj, W., Duan, W., Kelleher, K., et al. (2009). Investigation of leucine-rich repeat kinase 2: enzymological properties and novel assays. FEBS J. 276, 466-478. doi: 10.1111/j.1742-4658.2008.06789.x
2. Bekris, L. M., Mata, I. F., and Zabetian, C. P. (2010). The genetics of Parkinson disease. J. Geriatr. Psychiatry Neurol. 23, 228-242. doi: 10.1177/0891988710383572
3. Bella, J., Hindle, K. L., McEwan, P. A., and Lovell, S. C. (2008). The leucine-rich repeat structure. Cell. Mol. Life Sci.65, 2307-2333. doi: 10.1007/s00018-008-8019-0
4. Berger, Z., Smith, K. A., and Lavoie, M. J. (2010). Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochemistry 49, 5511-5523. doi: 10.1021/bi100157u
5. Bernards, A., and Settleman, J. (2004). GAP control: regulating the regulators of small GTPases. Trends Cell Biol.14, 377-385. doi: 10.1016/j.tcb.2004.05.003
6. Berwick, D. C., and Harvey, K. (2012). LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6. Hum. Mol. Genet. 21, 4966-4979. doi: 10.1093/hmg/dds342
7. Biosa, A., Trancikova, A., Civiero, L., Glauser, L., Bubacco, L., Greggio, E., et al. (2013). GTPase activity regulates kinase activity and cellular phenotypes of Parkinson's disease-associated LRRK2. Hum. Mol. Genet. 22, 1140-1156. doi: 10.1093/hmg/dds522
8. Bos, J. L., Rehmann, H., and Wittinghofer, A. (2007). Review GEFs and GAPs: critical elements in the control of small G proteins. Cell 129, 865-877. doi: 10.1016/j.cell.2007.05.018
9. Bosgraaf, L., and Van Haastert, P. J. M. (2003). Roc, a Ras/GTPase domain in complex proteins. Biochim. Biophys. Acta 1643, 5-10. doi: 10.1016/j.bbamcr.2003.08.008
10. Cardona, F., Tormos-Pérez, M., and Pérez-Tur, J. (2014). Structural and functional in silico analysis of LRRK2 missense substitutions. Mol. Biol. Rep. 41, 2529-2542. doi: 10.1007/s11033-014-3111-z
11. Chan, D., Citro, A., Cordy, J. M., Shen, G. C., and Wolozin, B. (2011). Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2). J. Biol. Chem. 286, 16140-16149. doi: 10.1074/jbc.M111.234005
12. Chavas, L. M. G., Torii, S., Kamikubo, H., Kawasaki, M., Ihara, K., Kato, R., et al. (2007). Structure of the small GTPase Rab27b shows an unexpected swapped dimer. Acta Crystallogr. D Biol. Crystallogr. 63, 769-779. doi: 10.1107/S0907444907019725
13. Choi, H. G., Zhang, J., Deng, X., Hatcher, J. M., Patricelli, M. P., Zhao, Z., et al. (2012). Brain Penetrant LRRK2 Inhibitor. ACS Med. Chem. Lett. 3, 658-662. doi: 10.1021/ml300123a
14. Cohen, P. (2002). Protein kinases-the major drug targets of the twenty-first century? Nat. Rev. Drug Discov. 1, 309-315. doi: 10.1038/nrd773
15. Cookson, M. R. (2010). The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat. Rev. Neurosci.11, 791-797. doi: 10.1038/nrn2935
16. Cookson, M. R., and Bandmann, O. (2010). Parkinson's disease: insights from pathways. Hum. Mol. Genet. 19, R21-R27. doi: 10.1093/hmg/ddq167
17. Csépányi-Kömi, R., Lévay, M., and Ligeti, E. (2012). Small G proteins and their regulators in cellular signalling. Mol. Cell. Endocrinol. 353, 10-20. doi: 10.1016/j.mce.2011.11.005
18. Dächsel, J. C., Behrouz, B., Yue, M., Beevers, J. E., Melrose, H. L., and Farrer, M. J. (2010). A comparative study of Lrrk2 function in primary neuronal cultures. Parkinsonism Relat. Disord. 16, 650-655. doi: 10.1016/j.parkreldis.2010.08.018
19. Deng, J., Lewis, P. A., Greggio, E., Sluch, E., Beilina, A., and Cookson, M. R. (2008). 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. 105, 1499-1504. doi: 10.1073/pnas.0709098105
20. Deng, X., Dzamko, N., Prescott, A., Davies, P., Liu, Q., Yang, Q., et al. (2011). Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat. Chem. Biol. 7, 203-205. doi: 10.1038/nchembio.538
21. Dzamko, N., Chua, G., Ranola, M., Rowe, D. B., and Halliday, G. M. (2013). Measurement of LRRK2 and Ser910/935 phosphorylated LRRK2 in peripheral blood mononuclear cells from idiopathic Parkinson's disease patients. J. Parkinsons Dis. 3, 145-152. doi: 10.3233/JPD-130174
22. Dzamko, N., Deak, M., Hentati, F., Reith, A. D., Prescott, A. R., Alessi, D. R., et al. (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. doi: 10.1042/BJ20100784
23. van Egmond, W. N., and van Haastert, P. J. M. (2010). Characterization of the Roco protein family in Dictyostelium discoideum. Eukaryot. Cell 9, 751-761. doi: 10.1128/EC.00366-09
24. Endicott, J. A., Noble, M. E. M., and Johnson, L. N. (2012). The structural basis for control of eukaryotic protein kinases. Annu. Rev. Biochem. 81, 587-613. doi: 10.1146/annurev-biochem-052410-090317
25. Fraser, K. B., Moehle, M. S., Daher, J. P. L., Webber, P. J., Williams, J. Y., Stewart, C. A., et al. (2013). LRRK2 secretion in exosomes is regulated by 14-3-3. Hum. Mol. Genet. 22, 4988-5000. doi: 10.1093/hmg/ddt346
26. Gasper, R., Meyer, S., Gotthardt, K., Sirajuddin, M., and Wittinghofer, A. (2009). It takes two to tango: regulation of G proteins by dimerization. Nat. Rev. Mol. Cell Biol. 10, 423-429. doi: 10.1038/nrm2689
27. Gilsbach, B. K., Ho, F. Y., Vetter, I. R., van Haastert, P. J. M., Wittinghofer, A., and Kortholt, A. (2012). Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations. Proc. Natl. Acad. Sci. U.S.A. 109, 10322-10327. doi: 10.1073/pnas.1203223109
28. Gotthardt, K., Weyand, M., Kortholt, A., Van Haastert, P. J. M., and Wittinghofer, A. (2008). Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase. EMBO J. 27, 2239-2249. doi: 10.1038/emboj.2008.150
29. Greggio, E., and Cookson, M. R. (2009). Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN Neuro 1, 13-24. doi: 10.1042/AN20090007
30. Greggio, E., Jain, S., Kingsbury, A., Bandopadhyay, R., Lewis, P., Kaganovich, A., et al. (2006). Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol. Dis. 23, 329-341. doi: 10.1016/j.nbd.2006.04.001
31. Greggio, E., Zambrano, I., Kaganovich, A., Beilina, A., Taymans, J.-M., Daniëls, V., et al. (2008). The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J. Biol. Chem. 283, 16906-16914. doi: 10.1074/jbc.M708718200
32. Guo, L., Gandhi, P. N., Wang, W., Petersen, R. B., Wilson-Delfosse, A. L., and Chen, S. G. (2007). The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. Exp. Cell Res. 313, 3658-3670. doi: 10.1016/j.yexcr.2007.07.007
33. Häbig, K., Gellhaar, S., Heim, B., Djuric, V., Giesert, F., Wurst, W., et al. (2013). LRRK2 guides the actin cytoskeleton at growth cones together with ARHGEF7 and Tropomyosin 4. Biochim. Biophys. Acta 1832, 2352-2367. doi: 10.1016/j.bbadis.2013.09.009
34. Herzig, M. C., Kolly, C., Persohn, E., Theil, D., Schweizer, T., Hafner, T., et al. (2011). LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum. Mol. Genet. 20, 4209-4223. doi: 10.1093/hmg/ddr348
35. Huse, M., and Kuriyan, J. (2002). The conformational plasticity of protein kinases. Cell 109, 275-282. doi: 10.1016/S0092-8674(02)00741-9
36. Iaccarino, C., Crosio, C., Vitale, C., Sanna, G., Carrì, M. T., and Barone, P. (2007). Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum. Mol. Genet. 16, 1319-1326. doi: 10.1093/hmg/ddm080
37. Ito, G., Okai, T., Fujino, G., Takeda, K., Ichijo, H., and Katada, T. (2007). GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson' s disease. Biochemistry 46, 1380-1388. doi: 10.1021/bi061960m
38. Jaleel, M., Nichols, R. J., Deak, M., Campbell, D. G., Gillardon, F., Knebel, A., et al. (2007). LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. Biochem. J.405, 307-317. doi: 10.1042/BJ20070209
39. Jorgensen, N. D., Peng, Y., Ho, C. C.-Y., Rideout, H. J., Petrey, D., Liu, P., et al. (2009). The WD40 domain is required for LRRK2 neurotoxicity. PLoS ONE 4:e8463. doi: 10.1371/journal.pone.0008463
40. Kawakami, F., Yabata, T., Ohta, E., Maekawa, T., Shimada, N., Suzuki, M., et al. (2012). LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth. PLoS ONE 7:e30834. doi: 10.1371/journal.pone.0030834
41. Kornev, A. P., Haste, N. M., Taylor, S. S., and Eyck, L. F. (2006). Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism. Proc. Natl. Acad. Sci. U.S.A. 103, 17783-17788. doi: 10.1073/pnas.0607656103
42. Lees, A. J., Hardy, J., and Revesz, T. (2009). Parkinson's disease. Lancet 373, 2055-2066. doi: 10.1016/S0140-6736(09)60492-X
43. Lewis, P. A., Greggio, E., Beilina, A., Jain, S., Baker, A., and Cookson, M. R. (2007). The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem. Biophys. Res. Commun. 357, 668-671. doi: 10.1016/j.bbrc.2007.04.006
44. Li, X., Moore, D. J., Xiong, Y., Dawson, T. M., and Dawson, V. L. (2010). Reevaluation of phosphorylation sites in the Parkinson disease-associated leucine-rich repeat kinase 2. J. Biol. Chem. 285, 29569-29576. doi: 10.1074/jbc.M110.127639
45. Li, X., Tan, Y.-C., Poulose, S., Olanow, C. W., Huang, X.-Y., and Yue, Z. (2007). Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants. J. Neurochem. 103, 238-247. doi: 10.1111/j.1471-4159.2007.04743.x
46. Liao, J., Wu, C., Burlak, C., Zhang, S., Sahm, H., Wang, M., et al. (2014). Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain. Proc. Natl. Acad. Sci. U.S.A. 111, 4055-4060. doi: 10.1073/pnas.1323285111
47. Liu, M., Dobson, B., Glicksman, M. A., Yue, Z., and Stein, R. L. (2010). Kinetic mechanistic studies of wild-type leucine-rich repeat kinase 2: characterization of the kinase and GTPase activities. Biochemistry 49, 2008-2017. doi: 10.1021/bi901851y
48. Lobbestael, E., Baekelandt, V., and Taymans, J.-M. (2012). Phosphorylation of LRRK2: from kinase to substrate. Biochem. Soc. Trans. 40, 1102-1110. doi: 10.1042/BST20120128
49. MacLeod, D., Dowman, J., Hammond, R., Leete, T., Inoue, K., and Abeliovich, A. (2006). The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52, 587-593. doi: 10.1016/j.neuron.2006.10.008
50. Manning, G., Whyte, D. B., Martinez, R., Hunter, T., and Sudarsanam, S. (2002). The protein kinase complement of the human genome. Science 298, 1912-1934. doi: 10.1126/science.1075762
51. Marín, I., van Egmond, W. N., and van Haastert, P. J. M. (2008). The Roco protein family: a functional perspective. FASEB J. 22, 3103-3110. doi: 10.1096/fj.08-111310
52. Mills, R. D., Mulhern, T. D., Liu, F., Culvenor, J. G., and Cheng, H.-C. (2014). Prediction of the repeat domain structures and impact of Parkinsonism-associated variations on structure and function of all functional domains of leucine-rich repeat kinase 2 (LRRK2). Hum. Mutat. 35, 395-412. doi: 10.1002/humu.22515
53. Mosavi, L., and Cammett, T. (2004). The ankyrin repeat as molecular architecture for protein recognition. Protein Sci. 13, 1435-1448. doi: 10.1110/ps.03554604.ity
54. Ness, D., Ren, Z., Gardai, S., Sharpnack, D., Johnson, V. J., Brennan, R. J., et al. (2013). Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis. PLoS ONE 8:e66164. doi: 10.1371/journal.pone.0066164
55. Nichols, R. J., Dzamko, N., Morrice, N. A., Campbell, D. G., Deak, M., Ordureau, A., et al. (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. doi: 10.1042/BJ20100483
56. Ohta, E., Kubo, M., and Obata, F. (2010). Prevention of intracellular degradation of I2020T mutant LRRK2 restores its protectivity against apoptosis. Biochem. Biophys. Res. Commun. 391, 242-247. doi: 10.1016/j.bbrc.2009.11.043
57. Paisán-Ruíz, C., Jain, S., Evans, E. W., Gilks, W. P., Simón, J., van der Brug, M., et al. (2004). Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595-600. doi: 10.1016/j.neuron.2004.10.023
58. Papkovskaia, T. D., Chau, K.-Y., Inesta-Vaquera, F., Papkovsky, D. B., Healy, D. G., Nishio, K., et al. (2012). G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization. Hum. Mol. Genet.21, 4201-4213. doi: 10.1093/hmg/dds244
59. Ramsden, N., Perrin, J., Ren, Z., Lee, B. D., Zinn, N., Dawson, V. L., et al. (2011). Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons. ACS Chem. Biol. 6, 1021-1028.
60. Reith, A. D., Bamborough, P., Jandu, K., Andreotti, D., Mensah, L., Dossang, P., et al. (2012). GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg. Med. Chem. Lett. 22, 5625-5629. doi: 10.1016/j.bmcl.2012.06.104
61. Rudenko, I. N., Kaganovich, A., Hauser, D. N., Beylina, A., Chia, R., Ding, J., et al. (2012). The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation. Biochem. J.446, 99-111. doi: 10.1042/BJ20120637
62. Sancho, R. M., Law, B. M. H., and Harvey, K. (2009). Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways. Hum. Mol. Genet. 18, 3955-3968. doi: 10.1093/hmg/ddp337
63. Scheffzek, K. (1997). The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic ras mutants. Science 277, 333-338. doi: 10.1126/science.277.5324.333
64. Smith, W. W., Pei, Z., Jiang, H., Dawson, V. L., Dawson, T. M., and Ross, C. A. (2006). Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat. Neurosci. 9, 1231-1233. doi: 10.1038/nn1776
65. Stafa, K., Trancikova, A., Webber, P. J., Glauser, L., West, A. B., and Moore, D. J. (2012). GTPase activity and neuronal toxicity of Parkinson's disease-associated LRRK2 is regulated by ArfGAP1. PLoS Genet. 8:e1002526. doi: 10.1371/journal.pgen.1002526
66. Taylor, S. S., and Kornev, A. P. (2011). Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem. Sci. 36, 65-77. doi: 10.1016/j.tibs.2010.09.006
67. Taymans, J.-M. (2012). The GTPase function of LRRK2. Biochem. Soc. Trans. 40, 1063-1069. doi: 10.1042/BST20120133
68. Tewari, R., Bailes, E., Bunting, K. A., and Coates, J. C. (2010). Armadillo-repeat protein functions: questions for little creatures. Trends Cell Biol. 20, 470-481. doi: 10.1016/j.tcb.2010.05.003
69. Tong, Y., Giaime, E., Yamaguchi, H., Ichimura, T., Liu, Y., Si, H., et al. (2012). Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol. Neurodegener. 7, 2. doi: 10.1186/1750-1326-7-2
70. Vancraenenbroeck, R., Lobbestael, E., Weeks, S. D., Strelkov, S. V., Baekelandt, V., Taymans, J.-M., et al. (2012). Expression, purification and preliminary biochemical and structural characterization of the leucine rich repeat namesake domain of leucine rich repeat kinase 2. Biochim. Biophys. Acta 1824, 450-460. doi: 10.1016/j.bbapap.2011.12.009
71. Vetter, I. R., and Wittinghofer, A. (2001). The guanine nucleotide-binding switch in three dimensions. Science 294, 1299-1304. doi: 10.1126/science.1062023
72. Wan, P. T. C., Garnett, M. J., Roe, S. M., Lee, S., Niculescu-Duvaz, D., Good, V. M., et al. (2004). Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855-867. doi: 10.1016/S0092-8674(04)00215-6
73. West, A. B., Moore, D. J., Biskup, S., Bugayenko, A., Smith, W. W., Ross, C. A., et al. (2005). Parkinson ' s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad Sci. U.S.A. 102, 16842-16847. doi: 10.1073/pnas.0507360102
74. Winner, B., Melrose, H. L., Zhao, C., Hinkle, K. M., Yue, M., Kent, C., et al. (2011). Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol. Dis. 41, 706-716. doi: 10.1016/j.nbd.2010.12.008
75. Xiong, Y., Yuan, C., Chen, R., Dawson, T. M., and Dawson, V. L. (2012). ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2. J. Neurosci. 32, 3877-3886. doi: 10.1523/JNEUROSCI.4566-11.2012
76. Xu, C., and Min, J. (2011). Structure and function of WD40 domain proteins. Protein Cell 2, 202-214. doi: 10.1007/s13238-011-1018-1
77. Yao, C., Johnson, W. M., Gao, Y., Wang, W., Zhang, J., Deak, M., et al. (2013). Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2 toxicity. Hum. Mol. Genet. 22, 328-344. doi: 10.1093/hmg/dds431
78. Zhang, J., Deng, X., Choi, H. G., Alessi, D. R., and Gray, N. S. (2012). Characterization of TAE684 as a potent LRRK2 kinase inhibitor. Bioorg. Med. Chem. Lett. 22, 1864-1869. doi: 10.1016/j.bmcl.2012.01.084
79. Zhao, J., Hermanson, S. B., Carlson, C. B., Riddle, S. M., Vogel, K. W., Bi, K., et al. (2012). Pharmacological inhibition of LRRK2 cellular phosphorylation sites provides insight into LRRK2 biology. Biochem. Soc. Trans. 40, 1158-1162. doi: 10.1042/BST20120137
80. Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., et al. (2004). Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601-607. doi: 10.1016/j.neuron.2004.11.005