Unique functional and structural properties of the LRRK2 protein ATP-binding pocket

Journal of Biological Chemistry

Volumn 289, Issue 47, 2014, Pages 32937-32951

  Liu, Zhiyong ^a,b   Galemmo, Robert A ^c   Fraser, Kyle B ^a   Moehle, Mark S ^a   Sen, Saurabh ^a   Volpicelli Daley, Laura A ^a   DeLucas, Lawrence J ^c   Ross, Larry J ^c   Valiyaveettil, Jacob ^c   Moukha Chafiq, Omar ^c   Pathak, Ashish K ^c   Ananthan, Subramaniam ^c   Kezar, Hollis ^c   White, E Lucile ^c   Gupta, Vandana ^c   Maddry, Joseph A ^c   Suto, Mark J ^c   West, Andrew B ^a  

^a UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

^b UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

^c SOUTHERN RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

NEURONS; PEPTIDES; PHOSPHORYLATION; PROBES; PROTEINS;

HIGH-RESOLUTION STRUCTURES; HIGH-THROUGHPUT ANALYSIS; HIGH-THROUGHPUT ASSAYS; PEPTIDE PHOSPHORYLATION; PROINFLAMMATORY RESPONSE; SMALL MOLECULE INHIBITOR; STRUCTURAL CONFIGURATIONS; STRUCTURE ACTIVITY RELATIONSHIPS;

ENZYMES;

ADENOSINE TRIPHOSPHATE; LEUCINE RICH REPEAT KINASE 2; PROTEIN KINASE INHIBITOR; SRI 29132; UNCLASSIFIED DRUG; 1-(PIPERIDIN-1-YL)-2-((3-(THIOPHEN-2-YL)-(1,2,4)TRIAZOLO(4,3-B)PYRIDAZIN-6-YL)THIO)BUTAN-1-ONE; LRRK2 PROTEIN, HUMAN; MOLECULAR LIBRARY; PROTEIN BINDING; PROTEIN SERINE THREONINE KINASE; PYRIDAZINE DERIVATIVE; TRIAZOLE DERIVATIVE;

ANIMAL CELL; ARTICLE; AUTOPHOSPHORYLATION; BINDING SITE; BLOOD BRAIN BARRIER; BRAIN NERVE CELL; COMPUTER MODEL; CONTROLLED STUDY; DRUG SELECTIVITY; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; ESCHERICHIA COLI; HUMAN; LEUCINE RICH REPEAT KINASE 2 ADENOSINE TRIPHOSPHATE BINDING POCKET; MACROPHAGE; MOUSE; NEURITE; NONHUMAN; PHENOTYPE; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN STRUCTURE; STRUCTURE ACTIVITY RELATION; WESTERN BLOTTING; AMINO ACID SEQUENCE; ANIMAL; BIOCATALYSIS; CELL CULTURE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; GENETICS; HEPG2 CELL LINE; KINETICS; METABOLISM; MOLECULAR GENETICS; MOLECULAR LIBRARY; MUTATION; PHARMACOLOGY; PHOSPHORYLATION; PROTEIN TERTIARY STRUCTURE; SEQUENCE HOMOLOGY; TUMOR CELL LINE;

ADENOSINE TRIPHOSPHATE; AMINO ACID SEQUENCE; ANIMALS; BINDING SITES; BIOCATALYSIS; BLOTTING, WESTERN; CELL LINE, TUMOR; CELLS, CULTURED; HEP G2 CELLS; HUMANS; KINETICS; MICE; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MOLECULAR STRUCTURE; MUTATION; PHOSPHORYLATION; PROTEIN BINDING; PROTEIN KINASE INHIBITORS; PROTEIN STRUCTURE, TERTIARY; PROTEIN-SERINE-THREONINE KINASES; PYRIDAZINES; SEQUENCE HOMOLOGY, AMINO ACID; SMALL MOLECULE LIBRARIES; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZOLES;

EID: 84911363804     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.602318     Document Type: Article

References (45)

1. 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
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. 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
4. 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
5. Cookson, M. R. (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat. Rev. Neurosci. 11, 791-797
6. 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) Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci. Transl. Med. 4, 164ra161
7. 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
8. 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
9. Ray, S., Bender, S., Kang, S., Lin, R., Glicksman, M. A., and Liu, M. (2014) The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity. J. Biol. Chem. 289, 13042-13053
10. Liao, J., Wu, C. X., Burlak, C., Zhang, S., Sahm, H., Wang, M., Zhang, Z. Y., Vogel, K. W., Federici, M., Riddle, S. M., Nichols, R. J., Liu, D., Cookson, M. R., Stone, T. A., and Hoang, Q. Q. (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
11. 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
12. 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
13. Baptista, M. A., Dave, K. D., Frasier, M. A., Sherer, T. B., Greeley, M., Beck, M. J., Varsho, J. S., Parker, G. A., Moore, C., Churchill, M. J., Meshul, C. K., and Fiske, B. K. (2013) Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs. PLoS ONE 8, e80705
14. Tong, Y., Yamaguchi, H., Giaime, E., Boyle, S., Kopan, R., Kelleher, R. J., 3rd, and Shen, J. (2010) Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice. Proc. Natl. Acad. Sci. U.S.A. 107, 9879-9884
15. Andres-Mateos, E., Mejias, R., Sasaki, M., Li, X., Lin, B. M., Biskup, S., Zhang, L., Banerjee, R., Thomas, B., Yang, L., Liu, G., Beal, M. F., Huso, D. L., Dawson, T. M., and Dawson, V. L. (2009) Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). J. Neurosci. 29, 15846-15850
16. 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
17. Covy, J. P., and Giasson, B. I. (2009) Identification of compounds that inhibit the kinase activity of leucine-rich repeat kinase 2. Biochem. Biophys. Res. Commun. 378, 473-477
18. 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
19. Ramsden, N., Perrin, J., Ren, Z., Lee, B. D., Zinn, N., Dawson, V. L., Tam, D., Bova, M., Lang, M., Drewes, G., Bantscheff, M., Bard, F., Dawson, T. M., and Hopf, C. (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
20. 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
21. Lee, B. D., Shin, J. H., VanKampen, J., Petrucelli, L., West, A. B., Ko, H. S., Lee, Y. I., Maguire-Zeiss, K. A., Bowers, W. J., Federoff, H. J., Dawson, V. L., and Dawson, T. M. (2010) Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nat. Med. 16, 998-1000
22. Deng, X., Dzamko, N., Prescott, A., Davies, P., Liu, Q., Yang, Q., Lee, J. D., Patricelli, M. P., Nomanbhoy, T. K., Alessi, D. R., and Gray, N. S. (2011) Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat. Chem. Biol. 7, 203-205
23. Reith, A. D., Bamborough, P., Jandu, K., Andreotti, D., Mensah, L., Dossang, P., Choi, H. G., Deng, X., Zhang, J., Alessi, D. R., and Gray, N. S. (2012) GSK2578215A: a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg. Med. Chem. Lett. 22, 5625-5629
24. Choi, H. G., Zhang, J., Deng, X., Hatcher, J. M., Patricelli, M. P., Zhao, Z., Alessi, D. R., and Gray, N. S. (2012) Brain penetrant LRRK2 inhibitor. ACS Med. Chem. Lett. 3, 658-662
25. 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
26. Greggio, E., Zambrano, I., Kaganovich, A., Beilina, A., Taymans, J. M., Daniëls, 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
27. Stafa, K., Tsika, E., Moser, R., Musso, A., Glauser, L., Jones, A., Biskup, S., Xiong, Y., Bandopadhyay, R., Dawson, V. L., Dawson, T. M., and Moore, D. J. (2014) Functional interaction of Parkinson's disease-associated LRRK2 with members of the dynamin GTPase superfamily. Hum. Mol. Genet. 23, 2055-2077
28. 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
29. Volpicelli-Daley, L. A., Luk, K. C., Patel, T. P., Tanik, S. A., Riddle, D. M., Stieber, A., Meaney, D. F., Trojanowski, J. Q., and Lee, V. M. (2011) Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57-71
30. Smith, W. W., Pei, Z., Jiang, H., Moore, D. J., Liang, Y., West, A. B., Dawson, V. L., Dawson, T. M., and Ross, C. A. (2005) Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl. Acad. Sci. U.S.A. 102, 18676-18681
31. Vallotton, P., Lagerstrom, R., Sun, C., Buckley, M., Wang, D., De Silva, M., Tan, S. S., and Gunnersen, J. M. (2007) Automated analysis of neurite branching in cultured cortical neurons using HCA-Vision. Cytometry A 71, 889-895
32. Franzini, M., Ye, X. M., Adler, M., Aubele, D. L., Garofalo, A. W., Gauby, S., Goldbach, E., Probst, G. D., Quinn, K. P., Santiago, P., Sham, H. L., Tam, D., Truong, A., and Ren, Z. (2013) Triazolopyridazine LRRK2 kinase inhibitors. Bioorg. Med. Chem. Lett. 23, 1967-1973
33. Treiber, D. K., and Shah, N. P. (2013) Ins and outs of kinase DFG motifs. Chem. Biol. 20, 745-746
34. 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
35. Moehle, M. S., Webber, P. J., Tse, T., Sukar, N., Standaert, D. G., DeSilva, T. M., Cowell, R. M., and West, A. B. (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J. Neurosci. 32, 1602-1611
36. Thévenet, J., Pescini Gobert, R., Hooft van Huijsduijnen, R., Wiessner, C., and Sagot, Y. J. (2011) Regulation of LRRK2 expression points to a functional role in human monocyte maturation. PLoS ONE 6, e21519
37. Hakimi, M., Selvanantham, T., Swinton, E., Padmore, R. F., Tong, Y., Kabbach, G., Venderova, K., Girardin, S. E., Bulman, D. E., Scherzer, C. R., LaVoie, M. J., Gris, D., Park, D. S., Angel, J. B., Shen, J., Philpott, D. J., and Schlossmacher, M. G. (2011) Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J. Neural Transm. 118, 795-808
38. Misra, S., Ujházy, P., Varticovski, L., and Arias, I. M. (1999) Phosphoinositide 3-kinase lipid products regulate ATP-dependent transport by sister of P-glycoprotein and multidrug resistance associated protein 2 in bile canalicular membrane vesicles. Proc. Natl. Acad. Sci. U.S.A. 96, 5814-5819
39. 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
40. Santner, A. A., Croy, C. H., Vasanwala, F. H., Uversky, V. N., Van, Y. Y., and Dunker, A. K. (2012) Sweeping away protein aggregation with entropic bristles: intrinsically disordered protein fusions enhance soluble expression. Biochemistry 51, 7250-7262
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
42. 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
43. Lemaire, S., Van Bambeke, F., Mingeot-Leclercq, M. P., and Tulkens, P. M. (2007) Modulation of the cellular accumulation and intracellular activity of daptomycin towards phagocytized Staphylococcus aureus by the P-glycoprotein (MDR1) efflux transporter in human THP-1 macrophages and Madin-Darby canine kidney cells. Antimicrob. Agents Chemother. 51, 2748-2757
44. Daher, J. P., Volpicelli-Daley, L. A., Blackburn, J. P., Moehle, M. S., and West, A. B. (2014) Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc. Natl. Acad. Sci. U.S.A. 111, 9289-9294
45. Sheng, D., Qu, D., Kwok, K. H., Ng, S. S., Lim, A. Y., Aw, S. S., Lee, C. W., Sung, W. K., Tan, E. K., Lufkin, T., Jesuthasan, S., Sinnakaruppan, M., and Liu, J. (2010) Deletion of the WD40 domain of LRRK2 in Zebrafish causes Parkinsonism-like loss of neurons and locomotive defect. PLoS Genet. 6, e1000914