Membrane localization of LRRK2 is associated with increased formation of the highly active lrrk2 dimer and changes in its phosphorylation

Biochemistry

Volumn 49, Issue 26, 2010, Pages 5511-5523

  Berger, Zdenek ^a,b   Smith, Kelsey A ^a   Lavoie, Matthew J ^a,b  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOSOMAL DOMINANTS; BIOCHEMICAL PROPERTIES; CELLULAR MECHANISMS; COMPLEX ASSEMBLY; CYTOSOLIC; KINASE ACTIVITY; LEUCINE-RICH REPEATS; MEMBRANE ASSOCIATION; MEMBRANE LOCALIZATION; MULTIPLE DOMAINS; PARKINSONS DISEASE; POST-TRANSLATIONAL MODIFICATIONS; PRIMARY FUNCTIONS; PROTEIN-PROTEIN INTERACTIONS; SMALL MOLECULE INHIBITOR; SUBCELLULAR LOCALIZATIONS; WILD TYPES;

AMINO ACIDS; ASSOCIATION REACTIONS; PHOSPHORYLATION; PROTEINS;

MEMBRANES;

DIMER; GUANOSINE TRIPHOSPHATE; LEUCINE RICH REPEAT KINASE 2;

ANIMAL TISSUE; ARTICLE; CELL MEMBRANE; CELLULAR DISTRIBUTION; CYTOSOL; ENZYME ACTIVITY; ENZYME LOCALIZATION; ENZYME PHOSPHORYLATION; HUMAN; HUMAN TISSUE; MOUSE; NONHUMAN; PRIMATE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; WILD TYPE;

CELL LINE; CELL MEMBRANE; CYTOSOL; ENZYME ACTIVATION; GUANOSINE TRIPHOSPHATE; HUMANS; PARKINSON DISEASE; PHOSPHORYLATION; PROTEIN BINDING; PROTEIN MULTIMERIZATION; PROTEIN TRANSPORT; PROTEIN-SERINE-THREONINE KINASES;

EID: 77954197844     PISSN: 00062960     EISSN: 15204995     Source Type: Journal    
DOI: 10.1021/bi100157u     Document Type: Article

References (61)

1. Thomas, B. and Beal, M. F. (2007) Parkinson's disease Hum. Mol. Genet. 16 (Special Issue No. 2) R183-R194
2. Farrer, M. J. (2006) Genetics of Parkinson disease: Paradigm shifts and future prospects Nat. Rev. Genet. 7, 306-318
3. Cookson, M. R., Xiromerisiou, G., and Singleton, A. (2005) How genetics research in Parkinson's disease is enhancing understanding of the common idiopathic forms of the disease Curr. Opin. Neurol. 18, 706-711
4. Melrose, H. (2008) Update on the functional biology of Lrrk2 Future Neurol. 3, 669-681
5. Paisan-Ruiz, C., Jain, S., Evans, E. W., Gilks, W. P., Simon, J., van der Brug, M., Lopez de Munain, A., Aparicio, S., Gil, A. M., Khan, N., Johnson, J., Martinez, J. R., Nicholl, D., Carrera, I. M., Pena, A. S., de Silva, R., Lees, A., Marti-Masso, J. F., Perez-Tur, J., Wood, N. W., and Singleton, A. B. (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease Neuron 44, 595-600
6. Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carbajal, I. C., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., and Gasser, T. (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology Neuron 44, 601-607
7. Healy, D. G., Falchi, M., OSullivan, S. S., Bonifati, V., Durr, A., Bressman, S., Brice, A., Aasly, J., Zabetian, C. P., Goldwurm, S., Ferreira, J. J., Tolosa, E., Kay, D. M., Klein, C., Williams, D. R., Marras, C., Lang, A. E., Wszolek, Z. K., Berciano, J., Schapira, A. H., Lynch, T., Bhatia, K. P., Gasser, T., Lees, A. J., and Wood, N. W. (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: A case-control study Lancet Neurol. 7, 583-590
8. Hulihan, M. M., Ishihara-Paul, L., Kachergus, J., Warren, L., Amouri, R., Elango, R., Prinjha, R. K., Upmanyu, R., Kefi, M., Zouari, M., Sassi, S. B., Yahmed, S. B., El Euch-Fayeche, G., Matthews, P. M., Middleton, L. T., Gibson, R. A., Hentati, F., and Farrer, M. J. (2008) LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: A case-control genetic study Lancet Neurol. 7, 591-594
9. Latourelle, J. C., Sun, M., Lew, M. F., Suchowersky, O., Klein, C., Golbe, L. I., Mark, M. H., Growdon, J. H., Wooten, G. F., Watts, R. L., Guttman, M., Racette, B. A., Perlmutter, J. S., Ahmed, A., Shill, H. A., Singer, C., Goldwurm, S., Pezzoli, G., Zini, M., Saint-Hilaire, M. H., Hendricks, A. E., Williamson, S., Nagle, M. W., Wilk, J. B., Massood, T., Huskey, K. W., Laramie, J. M., DeStefano, A. L., Baker, K. B., Itin, I., Litvan, I., Nicholson, G., Corbett, A., Nance, M., Drasby, E., Isaacson, S., Burn, D. J., Chinnery, P. F., Pramstaller, P. P., Al-hinti, J., Moller, A. T., Ostergaard, K., Sherman, S. J., Roxburgh, R., Snow, B., Slevin, J. T., Cambi, F., Gusella, J. F., and Myers, R. H. (2008) The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: The GenePD study BMC Med. 6, 32
10. Kay, D. M., Kramer, P., Higgins, D., Zabetian, C. P., and Payami, H. (2005) Escaping Parkinson's disease: A neurologically healthy octogenarian with the LRRK2 G2019S mutation Mov. Disord. 20, 1077-1078
11. Greggio, E. and Cookson, M. R. (2009) Leucine-rich repeat kinase 2 mutations and Parkinson's disease: Three questions ASN Neuro 1 e00002
12. 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. U.S.A. 102, 16842-16847
13. 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
14. Iaccarino, C., Crosio, C., Vitale, C., Sanna, G., Carri, M. T., and Barone, P. (2007) Apoptotic mechanisms in mutant LRRK2-mediated cell death Hum. Mol. Genet. 16, 1319-1326
15. Greggio, E., Jain, S., Kingsbury, A., Bandopadhyay, R., Lewis, P., Kaganovich, A., van der Brug, M. P., Beilina, A., Blackinton, J., Thomas, K. J., Ahmad, R., Miller, D. W., Kesavapany, S., Singleton, A., Lees, A., Harvey, R. J., Harvey, K., and Cookson, M. R. (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin Neurobiol. Dis. 23, 329-341
16. Lin, X., Parisiadou, L., Gu, X. L., Wang, L., Shim, H., Sun, L., Xie, C., Long, C. X., Yang, W. J., Ding, J., Chen, Z. Z., Gallant, P. E., Tao-Cheng, J. H., Rudow, G., Troncoso, J. C., Liu, Z., Li, Z., and Cai, H. (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant α-synuclein Neuron 64, 807-827
17. 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., and Dawson, T. M. (2007) Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity Hum. Mol. Genet. 16, 223-232
18. Anand, V. S., Reichling, L. J., Lipinski, K., Stochaj, W., Duan, W., Kelleher, K., Pungaliya, P., Brown, E. L., Reinhart, P. H., Somberg, R., Hirst, W. D., Riddle, S. M., and Braithwaite, S. P. (2009) Investigation of leucine-rich repeat kinase 2: Enzymological properties and novel assays FEBS J. 276, 466-478
19. Luzon-Toro, B., de la Torre, E. R., Delgado, A., Perez-Tur, J., and Hilfiker, S. (2007) Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation Hum. Mol. Genet. 16, 2031-2039
20. Gloeckner, C. J., Schumacher, A., Boldt, K., and Ueffing, M. (2009) The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro J. Neurochem. 109, 959-968
21. Biskup, S., Moore, D. J., Celsi, F., Higashi, S., West, A. B., Andrabi, S. A., Kurkinen, K., Yu, S. W., Savitt, J. M., Waldvogel, H. J., Faull, R. L., Emson, P. C., Torp, R., Ottersen, O. P., Dawson, T. M., and Dawson, V. L. (2006) Localization of LRRK2 to membranous and vesicular structures in mammalian brain Ann. Neurol. 60, 557-569
22. Hatano, T., Kubo, S., Imai, S., Maeda, M., Ishikawa, K., Mizuno, Y., and Hattori, N. (2007) Leucine-rich repeat kinase 2 associates with lipid rafts Hum. Mol. Genet. 16, 678-690
23. 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
24. Plowey, E. D., Cherra, S. J., Liu, Y. J., and Chu, C. T. (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells J. Neurochem. 105, 1048-1056
25. Shin, N., Jeong, H., Kwon, J., Heo, H. Y., Kwon, J. J., Yun, H. J., Kim, C. H., Han, B. S., Tong, Y., Shen, J., Hatano, T., Hattori, N., Kim, K. S., Chang, S., and Seol, W. (2008) LRRK2 regulates synaptic vesicle endocytosis Exp. Cell Res. 314, 2055-2065
26. Alegre-Abarrategui, J., Christian, H., Lufino, M., Mutihac, R., Lourenco Venda, L., Ansorge, O., and Wade-Martins, R. (2009) LRRK2 regulates autophagic activity and localises to specific membrane microdomains in a novel human genomic reporter cellular model Hum. Mol. Genet 18, 4022-4034
27. Sancho, R. M., Law, B. M., 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
28. Greggio, E., Zambrano, I., Kaganovich, A., Beilina, A., Taymans, J. M., Daniels, V., Lewis, P., Jain, S., Ding, J., Syed, A., Thomas, K. J., Baekelandt, V., and Cookson, M. R. (2008) The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation J. Biol. Chem. 283, 16906-16914
29. Gloeckner, C. J., Kinkl, N., Schumacher, A., Braun, R. J., ONeill, E., Meitinger, T., Kolch, W., Prokisch, H., and Ueffing, M. (2006) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity Hum. Mol. Genet. 15, 223-232
30. Klein, C. L., Rovelli, G., Springer, W., Schall, C., Gasser, T., and Kahle, P. J. (2009) Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment J. Neurochem. 111, 703-715
31. 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
32. LaVoie, M. J., Ostaszewski, B. L., Weihofen, A., Schlossmacher, M. G., and Selkoe, D. J. (2005) Dopamine covalently modifies and functionally inactivates parkin Nat. Med. 11, 1214-1221
33. 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
34. Greggio, E., Lewis, P. A., van der Brug, M. P., Ahmad, R., Kaganovich, A., Ding, J., Beilina, A., Baker, A. K., and Cookson, M. R. (2007) Mutations in LRRK2/dardarin associated with Parkinson disease are more toxic than equivalent mutations in the homologous kinase LRRK1 J. Neurochem. 102, 93-102
35. Korr, D., Toschi, L., Donner, P., Pohlenz, H. D., Kreft, B., and Weiss, B. (2006) LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain Cell. Signalling 18, 910-920
36. Ruxton, G. D. (2006) The unequal variance t-test is an underused alternative to Student's t-test and the Mann-Whitney U-test Behav. Ecol. 17, 688-690
37. Picton, C., Klee, C. B., and Cohen, P. (1980) Phosphorylase kinase from rabbit skeletal muscle: Identification of the calmodulin-binding subunits Eur. J. Biochem. 111, 553-561 (Pubitemid 11203322)
38. LaVoie, M. J., Fraering, P. C., Ostaszewski, B. L., Ye, W., Kimberly, W. T., Wolfe, M. S., and Selkoe, D. J. (2003) Assembly of the γ-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin J. Biol. Chem. 278, 37213-37222
39. Osenkowski, P., Li, H., Ye, W., Li, D., Aeschbach, L., Fraering, P. C., Wolfe, M. S., and Selkoe, D. J. (2009) Cryoelectron microscopy structure of purified γ-secretase at 12 Å resolution J. Mol. Biol. 385, 642-652
40. Gu, Y., Sanjo, N., Chen, F., Hasegawa, H., Petit, A., Ruan, X., Li, W., Shier, C., Kawarai, T., Schmitt-Ulms, G., Westaway, D., St George-Hyslop, P., and Fraser, P. E. (2004) The presenilin proteins are components of multiple membrane-bound complexes that have different biological activities J. Biol. Chem. 279, 31329-31336
41. Kimberly, W. T., LaVoie, M. J., Ostaszewski, B. L., Ye, W., Wolfe, M. S., and Selkoe, D. J. (2002) Complex N-linked glycosylated nicastrin associates with active γ-secretase and undergoes tight cellular regulation J. Biol. Chem. 277, 35113-35117
42. Kimberly, W. T., LaVoie, M. J., Ostaszewski, B. L., Ye, W., Wolfe, M. S., and Selkoe, D. J. (2003) γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2 Proc. Natl. Acad. Sci. U.S.A. 100, 6382-6387
43. Janssen, R. J., Nijtmans, L. G., van den Heuvel, L. P., and Smeitink, J. A. (2006) Mitochondrial complex I: Structure, function and pathology J. Inherited Metab. Dis. 29, 499-515
44. Sen, S., Webber, P. J., and West, A. B. (2009) Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization J. Biol. Chem. 284, 36346-36356
45. Klein, C. L., Rovelli, G., Springer, W., Schall, C., Gasser, T., and Kahle, P. J. (2009) Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment J. Neurochem. 111, 703-715
46. Jorgensen, N. D., Peng, Y., Ho, C. C., Rideout, H. J., Petrey, D., Liu, P., and Dauer, W. T. (2009) The WD40 domain is required for LRRK2 neurotoxicity PLoS One 4, e8463
47. 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
48. Ito, G., Okai, T., Fujino, G., Takeda, K., Ichijo, H., Katada, T., and Iwatsubo, 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
49. 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
50. Gallo, K. A. and Johnson, G. L. (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways Nat. Rev. Mol. Cell Biol. 3, 663-672
51. Ramos, J. W. (2008) The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells Int. J. Biochem. Cell Biol. 40, 2707-2719
52. Kyriakis, J. M. and Avruch, J. (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation Physiol. Rev. 81, 807-869
53. Greggio, E., Taymans, J. M., Zhen, E. Y., Ryder, J., Vancraenenbroeck, R., Beilina, A., Sun, P., Deng, J., Jaffe, H., Baekelandt, V., Merchant, K., and Cookson, M. R. (2009) The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites Biochem. Biophys. Res. Commun. 389, 449-454
54. Kamikawaji, S., Ito, G., and Iwatsubo, T. (2009) Identification of the autophosphorylation sites of LRRK2 Biochemistry 48, 10963-10975
55. Goodman, T., Schulenberg, B., Steinberg, T. H., and Patton, W. F. (2004) Detection of phosphoproteins on electroblot membranes using a small-molecule organic fluorophore Electrophoresis 25, 2533-2538
56. 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
57. Lovitt, B., Vanderporten, E. C., Sheng, Z., Zhu, H., Drummond, J., and Liu, Y. (2010) Differential effects of divalent manganese and magnesium on the kinase activity of leucine-rich repeat kinase 2 (LRRK2) Biochemistry 49, 3092-3100
58. Nichols, R. J., Dzamko, N., Hutti, J. E., Cantley, L. C., Deak, M., Moran, J., Bamborough, P., Reith, A. D., and Alessi, D. R. (2009) Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease Biochem. J. 424, 47-60
59. Blom, N., Gammeltoft, S., and Brunak, S. (1999) Sequence and structure-based prediction of eukaryotic protein phosphorylation sites J. Mol. Biol. 294, 1351-1362
60. Liou, A. K., Leak, R. K., Li, L., and Zigmond, M. J. (2008) Wild-type LRRK2 but not its mutant attenuates stress-induced cell death via ERK pathway Neurobiol. Dis. 32, 116-124
61. Raman, M., Chen, W., and Cobb, M. H. (2007) Differential regulation and properties of MAPKs Oncogene 26, 3100-3112