The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity

Journal of Biological Chemistry

Volumn 289, Issue 19, 2014, Pages 13042-13053

  Ray, Soumya ^a   Bender, Samantha ^a,b   Kang, Stephanie ^a,b   Lin, Regina ^a,b   Glicksman, Marcie A ^a,b   Liu, Min ^a,b  

^a The Harvard Center for Neurodegeneration & Repair   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACIDS; DATA TRANSFER RATES; PHOSPHORYLATION;

ACTIVATION LOOPS; COMPETITIVE MECHANISMS; KINASE ACTIVITY; LEUCINE-RICH REPEATS; PHOSPHORYL TRANSFER; PRODUCT RELEASE; PROTEIN MUTATIONS; RATE-LIMITING STEPS;

ENZYMES;

ADENOSINE TRIPHOSPHATE; LEUCINE RICH REPEAT KINASE 2;

ARTICLE; BINDING AFFINITY; BINDING SITE; CONTROLLED STUDY; ENZYME ACTIVATION; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME BINDING; ENZYME CONFORMATION; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; ENZYME STABILITY; ENZYME STRUCTURE; HYDROGEN BOND; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN DOMAIN; STEADY STATE;

ENZYME INHIBITORS; ENZYME KINETICS; LRRK2; MOLECULAR MODELING; PARKINSON DISEASE;

ADENOSINE TRIPHOSPHATE; AMINO ACID SUBSTITUTION; ANIMALS; ENZYME STABILITY; HUMANS; MODELS, BIOLOGICAL; MODELS, MOLECULAR; MUTATION, MISSENSE; PARKINSON DISEASE; PHOSPHORYLATION; PROTEIN STRUCTURE, TERTIARY; PROTEIN-SERINE-THREONINE KINASES;

EID: 84900463278     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M113.537811     Document Type: Article

References (54)

1. Moore, D. J., West, A. B., Dawson, V. L., and Dawson, T. M. (2005) Molecular pathophysiology of Parkinson's disease. Annu. Rev. Neurosci. 28, 57-87
2. Paisán-Ruíz, C., Jain, S., Evans, E. W., Gilks, W. P., Simón, J., Van Der Brug, M., López 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., Martí-Massó, J. F., Pérez-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
3. 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., Müller-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
4. Berg, D., Schweitzer, K. J., Leitner, P., Zimprich, A., Lichtner, P., Belcredi, P., Brüssel, T., Schulte, C., Maass, S., Nägele, T., Wszolek, Z. K., and Gasser, T. (2005) Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease. Brain 128, 3000-3011
5. Khan, N. L., Jain, S., Lynch, J. M., Pavese, N., Abou-Sleiman, P., Holton, J. L., Healy, D. G., Gilks, W. P., Sweeney, M. G., Ganguly, M., Gibbons, V., Gandhi, S., Vaughan, J., Eunson, L. H., Katzenschlager, R., Gayton, J., Lennox, G., Revesz, T., Nicholl, D., Bhatia, K. P., Quinn, N., Brooks, D., Lees, A. J., Davis, M. B., Piccini, P., Singleton, A. B., and Wood, N. W. (2005) Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 128, 2786-2796
6. Mata, I. F., Taylor, J. P., Kachergus, J., Hulihan, M., Huerta, C., Lahoz, C., Blazquez, M., Guisasola, L. M., Salvador, C., Ribacoba, R., Martinez, C., Farrer, M., and Alvarez, V. (2005) LRRK2 R1441G in Spanish patients with Parkinson's disease. Neurosci. Lett. 382, 309-311
7. 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
8. 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
9. 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, leucinerich repeat kinase 2(LRRK2), is an authentic GTPase that stimulates kinase activity. Exp. Cell Res. 313, 3658-3670
10. 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
11. 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
12. 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 GTPbinding and kinase activities to neuronal toxicity. Hum. Mol. Genet. 16, 223-232
13. Xiong, Y., Coombes, C. E., Kilaru, A., Li, X., Gitler, A. D., Bowers, W. J., Dawson, V. L., Dawson, T. M., and Moore, D. J. (2010) GTPase activity plays a key role in the pathobiology of LRRK2. PLoS Genet. 6, e1000902
14. 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
15. Gloeckner, C. J., Kinkl, N., Schumacher, A., Braun, R. J., O'Neill, 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
16. 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
17. Liu, M., Kang, S., Ray, S., Jackson, J., Zaitsev, A. D., Gerber, S. A., Cuny, G. D., and Glicksman, M. A. (2011) Kinetic, mechanistic, and structural modeling studies of truncated wild-type leucine-rich repeat kinase 2 and the G2019S mutant. Biochemistry 50, 9399-9408
18. Fiser, A., and Sali, A. (2003) ModLoop: automated modeling of loops in protein structures. Bioinformatics 19, 2500-2501
19. John, B., and Sali, A. (2003) Comparative protein structure modeling by iterative alignment, model building and model assessment. Nucleic Acids Res. 31, 3982-3992
20. Eswar, N., John, B., Mirkovic, N., Fiser, A., Ilyin, V. A., Pieper, U., Stuart, A. C., Marti-Renom, M. A., Madhusudhan, M. S., Yerkovich, B., and Sali, A. (2003) Tools for comparative protein structure modeling and analysis. Nucleic Acids Res. 31, 3375-3380
21. Sánchez, R., and Sali, A. (1997) Evaluation of comparative protein structure modeling by MODELLER-3. Proteins 1, 50-58
22. Liu, M., Bender, S. A., Cuny, G. D., Sherman, W., Glicksman, M., and Ray, S. S. (2013) Type II kinase inhibitors show an unexpected inhibition mode against Parkinson's disease-linked LRRK2 mutant G2019S. Biochemistry 52, 1725-1736
23. Gilsbach, B. K., Ho, F. Y., Vetter, I. R., Van Haastert, P. J., 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
24. Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J., Mainz, D. T., Repasky, M. P., Knoll, E. H., Shelley, M., Perry, J. K., Shaw, D. E., Francis, P., and Shenkin, P. S. (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem. 47, 1739-1749
25. Sherman, W., Day, T., Jacobson, M. P., Friesner, R. A., and Farid, R. (2006) Novel procedure for modeling ligand/receptor induced fit effects. J. Med. Chem. 49, 534-553
26. Jacobson, M. P., Pincus, D. L., Rapp, C. S., Day, T. J., Honig, B., Shaw, D. E., and Friesner, R. A. (2004) hierarchical approach to all-Atom protein loop prediction. Proteins 55, 351-367
27. Barducci, A., Bonomi, M., and Parrinello, M. (2010) Linking well tempered metadynamics simulations with experiments. Biophys. J. 98, L44-46
28. Barducci, A., Bussi, G., and Parrinello, M. (2008) Well tempered metadynamics: a smoothly converging and tunable free-energy method. Phys. Rev. Lett. 100, 020603
29. Barducci, A., Chelli, R., Procacci, P., Schettino, V., Gervasio, F. L., and Parrinello, M. (2006) Metadynamics simulation of prion protein: α-structure stability and the early stages of misfolding. J. Am. Chem. Soc. 128, 2705-2710
30. Berteotti, A., Barducci, A., and Parrinello, M. (2011) Effect of urea on the α-hairpin conformational ensemble and protein denaturation mechanism. J. Am. Chem. Soc. 133, 17200-17206
31. Bonomi, M., Barducci, A., Gervasio, F. L., and Parrinello, M. (2010) Multiple routes and milestones in the folding of HIV-1 protease monomer. PLoS One 5, e13208
32. Bonomi, M., and Parrinello, M. (2010) Enhanced sampling in the well tempered ensemble. Phys. Rev. Lett. 104, 190601
33. Branduardi, D., Gervasio, F. L., and Parrinello, M. (2007) From A to B in free energy space. J. Chem. Phys. 126, 054103
34. Bussi, G., Laio, A., and Parrinello, M. (2006) Equilibrium free energies from nonequilibrium metadynamics. Phys. Rev. Lett. 96, 090601
35. Leone, V., Marinelli, F., Carloni, P., and Parrinello, M. (2010) Targeting biomolecular flexibility with metadynamics. Curr. Opin. Struct. Biol. 20, 148-154
36. Limongelli, V., Bonomi, M., Marinelli, L., Gervasio, F. L., Cavalli, A., Novellino, E., and Parrinello, M. (2010) Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition. Proc. Natl. Acad. Sci. U. S. A. 107, 5411-5416
37. Limongelli, V., Marinelli, L., Cosconati, S., La Motta, C., Sartini, S., Mugnaini, L., Da Settimo, F., Novellino, E., and Parrinello, M. (2012) Sampling protein motion and solvent effect during ligand binding. Proc. Natl. Acad. Sci. U. S. A. 109, 1467-1472
38. Segel, I. H. (1975) Enzyme Kinetics, John Wiley & Sons, Inc., New York
39. Schindler, T., Bornmann, W., Pellicena, P., Miller, W. T., Clarkson, B., and Kuriyan, J. (2000) Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289, 1938-1942
40. Zhou, T., Commodore, L., Huang, W. S., Wang, Y., Thomas, M., Keats, J., Xu, Q., Rivera, V. M., Shakespeare, W. C., Clackson, T., Dalgarno, D. C., and Zhu, X. (2011) Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem. Biol. Drug Des. 77, 1-11
41. 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
42. Ray, S., and Liu, M. (2012) Current understanding of LRRK2 in Parkinson's disease: biochemical and structural features and inhibitor design. Future Med. Chem. 4, 1701-1713
43. Nichols, R. J., Dzamko, N., Morrice, N. A., Campbell, D. G., Deak, M., Ordureau, A., Macartney, T., Tong, Y., Shen, J., Prescott, A. R., and Alessi, D. R. (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
44. Sheng, Z., Zhang, S., Bustos, D., Kleinheinz, T., Le Pichon, C. E., Dominguez, S. L., Solanoy, H. O., Drummond, J., Zhang, X., Ding, X., Cai, F., Song, Q., Li, X., Yue, Z., Van Der Brug, M. P., Burdick, D. J., Gunzner-Toste, J., Chen, H., Liu, X., Estrada, A. A., Sweeney, Z. K., Scearce-Levie, K., Moffat, J. G., Kirkpatrick, D. S., and Zhu, H. (2012) Ser-1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci. Transl. Med. 4, 164ra161
45. Ohta, E., Katayama, Y., Kawakami, F., Yamamoto, M., Tajima, K., Maekawa, T., Iida, N., Hattori, S., and Obata, F. (2009) I (2020) T leucinerich repeat kinase 2, the causative mutant molecule of familial Parkinson's disease, has a higher intracellular degradation rate than the wild-type molecule. Biochem. Biophys. Res. Commun. 390, 710-715
46. Kawakami, F., Yabata, T., Ohta, E., Maekawa, T., Shimada, N., Suzuki, M., Maruyama, H., Ichikawa, T., and Obata, F. (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
47. Bailey, R. M., Covy, J. P., Melrose, H. L., Rousseau, L., Watkinson, R., Knight, J., Miles, S., Farrer, M. J., Dickson, D. W., Giasson, B. I., and Lewis, J. (2013) LRRK2 phosphorylates novel tau epitopes and promotes tauopathy. Acta Neuropathol. 126, 809-827
48. 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
49. Reichling, L. J., and Riddle, S. M. (2009) Leucine-rich repeat kinase 2 mutants I2020T and G2019S exhibit altered kinase inhibitor sensitivity. Biochem. Biophys. Res. Commun. 384, 255-258
50. Garuti, L., Roberti, M., and Bottegoni, G. (2010) Non-ATP competitive protein kinase inhibitors. Curr. Med. Chem. 17, 2804-2821
51. Choi, H. G., Zhang, J., Weisberg, E., Griffin, J. D., Sim, T., and Gray, N. S. (2012) Development of "DFG-out" inhibitors of gatekeeper mutant kinases. Bioorg. Med. Chem. Lett. 22, 5297-5302
52. Zhang, J., Yang, P. L., and Gray, N. S. (2009) Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer 9, 28-39
53. Cox, S., Radzio-Andzelm, E., and Taylor, S. S. (1994) Domain movements in protein kinases. Curr. Opin. Struct. Biol. 4, 893-901
54. Johnson, D. A., Akamine, P., Radzio-Andzelm, E., Madhusudan, M., and Taylor, S. S. (2001) Dynamics of cAMP-dependent protein kinase. Chem. Rev. 101, 2243-2270