Identification and characterization of a leucine-rich repeat kinase 2 (LRRK2) consensus phosphorylation motif

PLoS ONE

Volumn 5, Issue 10, 2010, Pages

  Pungaliya, Pooja P ^a   Bai, Yuchen ^a   Lipinski, Kerri ^a   Anand, Vasanti S ^a   Sen, Saurabh ^b   Brown, Eugene L ^a,c   Bates, Brian ^a   Reinhart, Peter H ^a,d   West, Andrew B ^b   Hirst, Warren D ^a   Braithwaite, Steven P ^a,e  

^a PFIZER INC   (United States)

^b The University of Alabama at Birmingham   (United States)

^c Quicksilver Consultants   (United States)

^d Proteostasis Therapeutics   (United States)

^e Signum Biosciences   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GUANOSINE TRIPHOSPHATE; LEUCINE RICH REPEAT KINASE 2; LRRK2 PROTEIN, HUMAN; PROTEIN SERINE THREONINE KINASE;

ARTICLE; AUTOPHOSPHORYLATION; CELL CULTURE; CELL STRAIN HEK293; CONTROLLED STUDY; ENZYME ACTIVITY; ENZYME ANALYSIS; GENETIC TRANSFECTION; HYDROLYSIS; IN VITRO STUDY; MASS SPECTROMETRY; PROTEIN BINDING; PROTEIN MOTIF; SIGNAL TRANSDUCTION; CELL LINE; CHEMISTRY; HUMAN; LIQUID CHROMATOGRAPHY; METABOLISM; PHOSPHORYLATION; POLYACRYLAMIDE GEL ELECTROPHORESIS; TANDEM MASS SPECTROMETRY;

CELL LINE; CHROMATOGRAPHY, LIQUID; ELECTROPHORESIS, POLYACRYLAMIDE GEL; GUANOSINE TRIPHOSPHATE; HUMANS; HYDROLYSIS; PHOSPHORYLATION; PROTEIN BINDING; PROTEIN-SERINE-THREONINE KINASES; SIGNAL TRANSDUCTION; TANDEM MASS SPECTROMETRY;

EID: 78149435654     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0013672     Document Type: Article

References (75)

1. Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophys-iology of Parkinson's disease. Annu Rev Neurosci 28: 57-87.
2. Biskup S, Gerlach M, Kupsch A, Reichmann H, Riederer P, et al. (2008) Genes associated with Parkinson syndrome. J Neurol 255(Suppl 5): 8-17.
3. Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, et al. (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44: 595-600.
4. Zimprich A, Muller-Myhsok B, Farrer M, Leitner P, Sharma M, et al. (2004) The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval. Am J Hum Genet 74: 11-19.
5. Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA (2006) LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci 29: 286-293.
6. Giasson BI, Van Deerlin VM (2008) Mutations in LRRK2 as a cause of Parkinson's disease. Neurosignals 16: 99-105.
7. Anand VS, Reichling LJ, Lipinski K, Stochaj W, Duan W, et al. (2009) Investigation of leucine-rich repeat kinase 2: enzymological properties and novel assays. Febs J 276: 466-478.
8. West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, 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.
9. Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O'Neill E, et al. (2006) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet 15: 223-232.
10. Henchcliffe C, Beal MF (2008) Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 4: 600-609.
11. Schulz JB (2008) Update on the pathogenesis of Parkinson's disease. J Neurol 255(Suppl 5): 3-7.
12. Schulz JB, Dichgans J (1999) Molecular pathogenesis of movement disorders: are protein aggregates a common link in neuronal degeneration? Curr Opin Neurol 12: 433-439.
13. Lotharius J, Brundin P (2002) Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3: 932-942.
14. Roach ES (2007) Both postsynaptic and presynaptic dysfunction contribute to Parkinson disease: any mechanism will not do. Arch Neurol 64: 143.
15. Lin X, Parisiadou L, Gu XL, Wang L, Shim H, et al. (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 64: 807-827.
16. Imai Y, Gehrke S, Wang HQ, Takahashi R, Hasegawa K, et al. (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. Embo J 27: 2432-2443.
17. Shin N, Jeong H, Kwon J, Heo HY, Kwon JJ, et al. (2008) LRRK2 regulates synaptic vesicle endocytosis. Exp Cell Res 314: 2055-2065.
18. Turk BE, Hutti JE, Cantley LC (2006) Determining protein kinase substrate specificity by parallel solution-phase assay of large numbers of peptide substrates. Nat Protoc 1: 375-379.
19. Schaefer EM, Guimond S (1998) Detection of protein tyrosine kinase activity using a high-capacity streptavidin-coated membrane and optimized biotinylated peptide substrates. Anal Biochem 261: 100-112.
20. Li X, Tan YC, Poulose S, Olanow CW, Huang XY, et al. (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.
21. Lewis PA, Greggio E, Beilina A, Jain S, Baker A, et al. (2007) The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem Biophys Res Commun 357: 668-671.
22. Hill JJ, Davies MV, Pearson AA, Wang JH, Hewick RM, et al. (2002) The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. J Biol Chem 277: 40735-40741.
23. Bembom O, Keles S, van der Laan MJ. (2007) Supervised detection of conserved motifs in DNA sequences with cosmo. Stat Appl Genet Mol Biol 6: Article8.
24. Schneider TD, Stephens RM (1990) Sequence logos: a new way to display consensus sequences. Nucleic Acids Res 18: 6097-6100.
25. Sen S, Webber PJ, West AB (2009) Leucine-Rich Repeat Kinase 2 (LRRK2) Kinase Activity: Dependence on Dimerization. J Biol Chem.
26. Songyang Z, Lu KP, Kwon YT, Tsai LH, Filhol O, et al. (1996) A structural basis for substrate specificities of protein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1. Mol Cell Biol 16: 6486-6493.
27. Songyang Z, Blechner S, Hoagland N, Hoekstra MF, Piwnica-Worms H, et al. (1994) Use of an oriented peptide library to determine the optimal substrates of protein kinases. Curr Biol 4: 973-982.
28. Hutti JE, Jarrell ET, Chang JD, Abbott DW, Storz P, et al. (2004) A rapid method for determining protein kinase phosphorylation specificity. Nat Methods 1: 27-29.
29. Nichols RJ, Dzamko N, Hutti JE, Cantley LC, Deak M, et al. (2009) Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease. Biochem J 424: 47-60.
30. West AB, Moore DJ, Choi C, Andrabi SA, Li X, 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.
31. Fujii K, Zhu G, Liu Y, Hallam J, Chen L, et al. (2004) Kinase peptide specificity: improved determination and relevance to protein phosphorylation. Proc Natl Acad Sci U S A 101: 13744-13749.
32. Crooks GE, Hon G, Chandonia JM, Brenner SE (2004) WebLogo: a sequence logo generator. Genome Res 14: 1188-1190.
33. Jaleel M, Nichols RJ, Deak M, Campbell DG, Gillardon F, et al. (2007) LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. Biochem J 405: 307-317.
34. Obenauer JC, Cantley LC, Yaffe MB (2003) Scansite 2.0: Proteome-wide prediction of cell signaling interactions using short sequence motifs. Nucleic Acids Res 31: 3635-3641.
35. Kamikawaji S, Ito G, Iwatsubo T (2009) Identification of the autopho-sphorylation sites of LRRK2. Biochemistry 48: 10963-10975.
36. Greggio E, Taymans JM, Zhen EY, Ryder J, Vancraenenbroeck R, et al. (2009) The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites. Biochem Biophys Res Commun 389: 449-454.
37. Gloeckner CJ, Boldt K, von Zweydorf F, Helm S, Wiesent L, et al. Phosphopeptide analysis reveals two discrete clusters of phosphorylation in the N-terminus and the Roc domain of the Parkinson-disease associated protein kinase LRRK2. J Proteome Res 9: 1738-1745.
38. Klein CL, Rovelli G, Springer W, Schall C, Gasser T, et al. (2009) Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment. J Neurochem 111: 703-715.
39. Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, et al. (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.
40. Greggio E, Zambrano I, Kaganovich A, Beilina A, Taymans JM, 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.
41. Richter K, Brar S, Ray M, Pisitkun P, Bolland S, et al. (2009) Speckled-like pattern in the germinal center (SLIP-GC), a nuclear GTPase expressed in activation-induced deaminase-expressing lymphomas and germinal center B cells. J Biol Chem 284: 30652-30661.
42. Tu C, Zhou X, Tropea JE, Austin BP, Waugh DS, et al. (2009) Structure of ERA in complex with the 39 end of 16S rRNA: implications for ribosome biogenesis. Proc Natl Acad Sci U S A 106: 14843-14848.
43. Garcia-Regalado A, Guzman-Hernandez ML, Ramirez-Rangel I, Robles-Molina E, Balla T, et al. (2008) G protein-coupled receptor-promoted trafficking of Gbeta1gamma2 leads to AKT activation at endosomes via a mechanism mediated by Gbeta1gamma2-Rab11a interaction. Mol Biol Cell 19: 4188-4200.
44. Quan A, Robinson PJ (2005) Rapid purification of native dynamin I and colorimetric GTPase assay. Methods Enzymol 404: 556-569.
45. Karnoub AE, Weinberg RA (2008) Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9: 517-531.
46. McGrath JP, Capon DJ, Goeddel DV, Levinson AD (1984) Comparative biochemical properties of normal and activated human ras p21 protein. Nature 310: 644-649.
47. Trahey M, Milley RJ, Cole GE, Innis M, Paterson H, et al. (1987) Biochemical and biological properties of the human N-ras p21 protein. Mol Cell Biol 7: 541-544.
48. Guo L, Gandhi PN, Wang W, Petersen RB, Wilson-Delfosse AL, et al. (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.
49. Lower BH, Bischoff KM, Kennelly PJ (2000) The archaeon Sulfolobus solfataricus contains a membrane-associated protein kinase activity that preferentially phosphorylates threonine residues in vitro. J Bacteriol 182: 3452-3459.
50. O'Neill T, Dwyer AJ, Ziv Y, Chan DW, Lees-Miller SP, et al. (2000) Utilization of oriented peptide libraries to identify substrate motifs selected by ATM. J Biol Chem 275: 22719-22727.
51. Ho CC, Rideout HJ, Ribe E, Troy CM, Dauer WT (2009) The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration. J Neurosci 29: 1011-1016.
52. MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, et al. (2006) The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52: 587-593.
53. Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15: 2177-2196.
54. Yang DQ, Kastan MB (2000) Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1. Nat Cell Biol 2: 893-898.
55. Kumar A, Greggio E, Beilina A, Kaganovich A, Chan D, et al. The Parkinson's disease associated LRRK2 exhibits weaker in vitro phosphorylation of 4E-BP compared to autophosphorylation. PLoS One 5: e8730.
56. Jaeger PA, Wyss-Coray T (2009) All-you-can-eat: autophagy in neurodegener-ation and neuroprotection. Mol Neurodegener 4: 16.
57. Chan EY, Kir S, Tooze SA (2007) siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy. J Biol Chem 282: 25464-25474.
58. Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, et al. (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet 18: 4022-4034.
59. Plowey ED, Cherra SJ, 3rd, Liu YJ, Chu CT (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105: 1048-1056.
60. Dorsey FC, Rose KL, Coenen S, Prater SM, Cavett V, et al. (2009) Mapping the phosphorylation sites of Ulk1. J Proteome Res 8: 5253-5263.
61. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, et al. (2008) A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A 105: 10762-10767.
62. Dehmelt L, Halpain S (2005) The MAP2/Tau family of microtubule-associated proteins. Genome Biol 6: 204.
63. Roger B, Al-Bassam J, Dehmelt L, Milligan RA, Halpain S (2004) MAP2c, but not tau, binds and bundles F-actin via its microtubule binding domain. Curr Biol 14: 363-371.
64. Sanchez C, Diaz-Nido J, Avila J (2000) Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function. Prog Neurobiol 61: 133-168.
65. Parisiadou L, Xie C, Cho HJ, Lin X, Gu XL, et al. (2009) Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. J Neurosci 29: 13971-13980.
66. Yu P, Chen Y, Tagle DA, Cai T (2002) PJA1, encoding a RING-H2 finger ubiquitin ligase, is a novel human X chromosome gene abundantly expressed in brain. Genomics 79: 869-874.
67. Mishra L, Tully RE, Monga SP, Yu P, Cai T, et al. (1997) Praja1, a novel gene encoding a RING-H2 motif in mouse development. Oncogene 15: 2361-2368.
68. Sasaki A, Masuda Y, Iwai K, Ikeda K, Watanabe K (2002) A RING finger protein Praja1 regulates Dlx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msx-interacting MAGE/Necdin family protein, Dlxin-1. J Biol Chem 277: 22541-22546.
69. Huang Q, Figueiredo-Pereira ME Ubiquitin/proteasome pathway impairment in neurodegeneration: therapeutic implications. Apoptosis.
70. Hunter T (2007) The age of crosstalk: phosphorylation, ubiquitination, and beyond. Mol Cell 28: 730-738.
71. Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, et al. (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 9: 1231-1233.
72. Ito G, Okai T, Fujino G, Takeda K, Ichijo H, et al. (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.
73. Xiong Y, Coombes CE, Kilaru A, Li X, Gitler AD, et al. GTPase activity plays a key role in the pathobiology of LRRK2. PLoS Genet 6: e1000902.
74. Liu M, Dobson B, Glicksman MA, Yue Z, Stein RL Kinetic mechanistic studies of wild-type leucine-rich repeat kinase 2: characterization of the kinase and GTPase activities. Biochemistry 49: 2008-2017.
75. Paleologou KE, Schmid AW, Rospigliosi CC, Kim HY, Lamberto GR, et al. (2008) Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of alpha-synuclein. J Biol Chem 283: 16895-16905.