Dithiothreitol causes HIV-1 integrase dimer dissociation while agents interacting with the integrase dimer interface promote dimer formation

Biochemistry

Volumn 50, Issue 10, 2011, Pages 1567-1581

  Tsiang, Manuel ^a   Jones, Gregg S ^a   Hung, Magdeleine ^a   Samuel, Dharmaraj ^a   Novikov, Nikolai ^a   Mukund, Susmith ^a   Brendza, Katherine M ^a   Niedziela Majka, Anita ^a   Jin, Debi ^a   Liu, Xiaohong ^a   Mitchell, Michael ^a   Sakowicz, Roman ^a   Geleziunas, Romas ^a  

^a GILEAD SCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BINDING DOMAIN; BINDING SYSTEMS; COACTIVATORS; COFACTORS; DIMER DISSOCIATION; DIMER FORMATION; DIMER INTERFACE; DITHIOTHREITOL; DOSE RESPONSE; DOSE-RESPONSE CURVES; ENZYMATIC ACTIVITIES; EQUILIBRIUM BINDING; HIV-1 INTEGRASE; IN-VITRO; INTEGRASE; MATHEMATICAL MODELING; SECOND PLATEAU; SMALL MOLECULE INHIBITOR; SMALL MOLECULES; SUBUNIT EXCHANGE; THIOL GROUPS; TIME-RESOLVED FLUORESCENCE;

AMINO ACIDS; BINDING ENERGY; DIMERIZATION; DISSOCIATION; ENERGY TRANSFER; FLUORESCENCE; MONOMERS; PEPTIDES;

DIMERS;

DIMER; DITHIOTHREITOL; EPITOPE; HUMAN IMMUNODEFICIENCY VIRUS 1 INTEGRASE; HYDROXYL GROUP; INTEGRASE; LENS EPITHELIUM DERIVED GROWTH FACTOR; MONOMER; PEPTIDE DERIVATIVE; THIOL DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BINDING COMPETITION; CONTROLLED STUDY; DIMERIZATION; DISSOCIATION CONSTANT; DOSE RESPONSE; ENZYME ACTIVITY; ENZYME ASSAY; ENZYME BINDING; ENZYME KINETICS; ENZYME STABILITY; EQUILIBRIUM CONSTANT; HUMAN IMMUNODEFICIENCY VIRUS 1; MATHEMATICAL MODEL; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DOMAIN; PROTEIN PROTEIN INTERACTION;

DITHIOTHREITOL; HIV INTEGRASE; HIV-1; KINETICS; PROTEIN BINDING; PROTEIN MULTIMERIZATION;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 79952431596     PISSN: 00062960     EISSN: 15204995     Source Type: Journal    
DOI: 10.1021/bi101504w     Document Type: Article

References (63)

1. Brown, P. O. (1997) in Retroviruses (Coffin, J. M., Hughes, S. H., and Varmus, H. E., Eds.), pp 161 - 204, Cold Spring Harbor Laboratory, Plainview, NY.
2. Brown, P. O., Bowerman, B., Varmus, H. E., and Bishop, J. M. (1987) Correct integration of retroviral DNA in vitro Cell 49, 347-356
3. Bowerman, B., Brown, P. O., Bishop, J. M., and Varmus, H. E. (1989) A nucleoprotein complex mediates the integration of retroviral DNA Genes Dev. 3, 469-478
4. Ellison, V., Abrams, H., Roe, T., Lifson, J., and Brown, P. (1990) Human immunodeficiency virus integration in a cell free system J. Virol. 64, 2711-2715 (Pubitemid 20171258)
5. Farnet, C. M. and Bushman, F. D. (1997) HIV-1 cDNA integration: requirement of HMG I(Y) protein for function of preintegration complexes in vitro Cell 88, 483-492 (Pubitemid 27154413)
6. Bukrinsky, M. I., Sharova, N., McDonald, T. L., Pushkarskaya, T., Tarpley, W. G., and Stevenson, M. (1993) Association of integrase, matrix, and reverse transcriptase antigens of human immunodeficiency virus type 1 with viral nucleic acids following acute infection Proc. Natl. Acad. Sci. U. S. A. 90, 6125-6129 (Pubitemid 23191467)
7. Miller, M. D., Farnet, C. M., and Bushman, F. D. (1997) Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition J. Virol. 71, 5382-5390 (Pubitemid 27258214)
8. Heinzinger, N. K., Bukrinsky, M. I., Haggerty, S. A., Ragland, A. M., Kewalramani, V., Lee, M. A., Gendelman, H. E., Ratner, L., Stevenson, M., and Emerman, M. (1994) The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells Proc. Natl. Acad. Sci. U. S. A. 91, 7311-7315 (Pubitemid 24226853)
9. Lee, M. S. and Craigie, R. (1994) Protection of retroviral DNA from autointegration: involvement of a cellular factor Proc. Natl. Acad. Sci. U. S. A. 91, 9823-9827 (Pubitemid 24311900)
10. Kalpana, G. V., Marmon, S., Wang, W., Crabtree, G. R., and Goff, S. P. (1994) Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5 Science 266, 2002-2006
11. Chen, H. and Engelman, A. (1998) The barrier-to-autointegration protein is a host factor for HIV type 1 integration Proc. Natl. Acad. Sci. U. S. A. 95, 15270-15274 (Pubitemid 29018688)
12. Yung, E., Sorin, M., Pal, A., Craig, E., Morozov, A., Delattre, O., Kappes, J., Ott, D., and Kalpana, G. V. (2001) Inhibition of HIV-1 virion production by a transdominant mutant of integrase interactor 1 Nat. Med. 7, 920-926 (Pubitemid 32756429)
13. Violot, S., Hong, S. S., Rakotobe, D., Petit, C., Gay, B., Moreau, K., Billaud, G., Priet, S., Sire, J., Schwartz, O., Mouscadet, J. F., and Boulanger, P. (2003) The human polycomb group EED protein interacts with the integrase of human immunodeficiency virus type 1 J. Virol. 77, 12507-12522 (Pubitemid 37430647)
14. Cherepanov, P., Maertens, G., Proost, P., Devreese, B., Van Beeumen, J., Engelborghs, Y., De Clercq, E., and Debyser, Z. (2003) HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells J. Biol. Chem. 278, 372-381 (Pubitemid 36043586)
15. Maertens, G., Cherepanov, P., Pluymers, W., Busschots, K., De Clercq, E., Debyser, Z., and Engelborghs, Y. (2003) LEDGF/p75 is essential for nuclear and chromosomal targeting HIV-1 integrase in human cells J. Biol. Chem. 278, 33528-33539 (Pubitemid 37055807)
16. Llano, M., Delgado, S., Vanegas, M., and Poeschla, E. M. (2004) Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase J. Biol. Chem. 279, 55570-55577 (Pubitemid 40066560)
17. Llano, M., Vanegas, M., Fregoso, O., Saenz, D., Chung, S., Peretz, M., and Eric M. Poeschla, E. M. (2004) LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes J. Virol. 78, 9524-9537 (Pubitemid 39096559)
18. Bushman, F. D., Engelman, A., Palmer, I., Wingfield, P., and Craigie, R. (1993) Domains of the integrase protein of human immunodeficiency virus type 1 responsible for polynucleotidyl transfer and zinc binding Proc. Natl. Acad. Sci. U. S. A. 90, 3428-3432 (Pubitemid 23111379)
19. Cai, M., Zheng, R., Caffrey, M., Craigie, R., Clore, G. M., and Gronenborn, A. M. (1997) Solution structure of the N-terminal zinc binding domain of HIV-1 integrase Nat. Struct. Biol. 4, 567-577 (Pubitemid 27282153)
20. Zheng, R., Jenkins, T. M., and Craigie, R. (1996) Zinc folds the N-terminal domain of HIV-1 integrase, promotes multimerization, and enhances catalytic activity Proc. Natl. Acad. Sci. U. S. A. 93, 13659-13664 (Pubitemid 26424175)
21. 2+ promotes the self-association of human immunodeficiency virus type-1 integrase in vitro Biochemistry 36, 173-180 (Pubitemid 27024690)
22. Dyda, F., Hickman, A. B., Jenkins, T. M., Engelman, A., Craigie, R., and Davies, D. R. (1994) Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases Science 266, 1981-1986
23. Goldgur, Y., Dyda, F., Hickman, A. B., Jenkins, T. M., Craigie, R., and Davies, D. R. (1998) Three new structures of the core domain of HIV-1 integrase: an active site that binds magnesium Proc. Natl. Acad. Sci. U. S. A. 95, 9150-9154 (Pubitemid 28506200)
24. Andrake, M. D. and Skalka, A. M. (1995) Multimerization determinants reside in both the catalytic core and C terminus of avian sarcoma virus integrase J. Biol. Chem. 270, 29299-29306
25. Jenkins, T. M., Engelman, A., Ghirlando, R., and Craigie, R. (1996) A soluble active mutant of HIV-1 integrase: involvement of both the core and carboxyl-terminal domains in multimerization J. Biol. Chem. 271, 7712-7718
26. Deprez, E., Tauc, P., Leh, H., Mouscadet, J. F., Auclair, C., and Brochon, J. C. (2000) Oligomeric states of the HIV-1 integrase as measured by time-resolved fluorescence anisotropy Biochemistry 39, 9275-9284 (Pubitemid 30626319)
27. Deprez, E., Tauc, P., Leh, H., Mouscadet, J. F., Auclair, C., Hawkins, M. E., and Brochon, J. C. (2001) DNA binding induces dissociation of the multimeric form of HIV-1 integrase: a timeresolved fluorescence anisotropy study Proc. Natl Acad. Sci. U. S. A. 98, 10090-10095 (Pubitemid 32802979)
28. Ciuffi, A., Llano, M., Poeschla, E., Hoffmann, C., Leipzig, J., Shinn, P., Ecker, J., and Bushman, F. (2005) A role for LEDGF/p75 in targeting HIV DNA integration Nat. Med. 11, 1287-1289 (Pubitemid 41752906)
29. Cherepanov, P., Devroe, E., Silver, P. A., and Engelman, A. (2004) Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/ transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase J. Biol. Chem. 279, 48883-48892 (Pubitemid 39625769)
30. Vanegas, M., Llano, M., Delgado, S., Thompson, D., Peretz, M., and Poeschla, E. (2005) Identification of the LEDGF/p75 HIV-1 integrase interaction domain and NLS reveals NLS-independent chromatin tethering J. Cell Sci. 118, 1733-1743 (Pubitemid 40691901)
31. Cherepanov, P., Sun, Z.-Y. J., Rahman, S., Maertens, G., Wagner, G., and Engelman, A. (2005) Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75 Nat. Struct. Mol. Biol. 12, 526-532 (Pubitemid 43085883)
32. Cherepanov, P., Ambrosio, A. L. B., Rahman, S., Ellenberger, T., and Engelman, A. (2005) Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75 Proc. Natl. Acad. Sci. U. S. A. 102, 17308-17313 (Pubitemid 41740862)
33. Hare, S., Shun, M.-C., Gupta, S. S., Valkov, E., Engelman, A., and Cherepanov, P. (2009) A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75 PLoS Pathog. 5, 1-12
34. Hare, S., Di Nunzio, F., Labeja, A., Wang, J., Engelman, A., and Cherepanov, P. (2009) Structural basis for functional tetramerization of lentiviral integrase PLoS Pathog. 5 (7) e1000515
35. Emiliani, S., Mousnier, A., Busschots, K., Maroun, M., Van Maele, B., Tempe, D., Vandekerckhove, L., Moisant, F., Ben-Slama, L., Witvrouw, M., Christ, F., Rain, J. C., Dargemont, C., Debyser, Z., and Benarous, R. (2005) Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication J. Biol. Chem. 280, 25517-25523 (Pubitemid 40962257)
36. Busschots, K., Voet, A., De Maeyer, M., Rain, J.-C., Emiliani, S., Benarous, R., Desender, L., Debyser, Z., and Christ, F. (2007) Identification of the LEDGF/p75 binding site in HIV-1 integrase J. Mol. Biol. 365, 1480-1492 (Pubitemid 46070174)
37. Rahman, S., Lu, R., Vandegraaff, N., Cherepanov, P., and Engelman, A. (2007) Structure-based mutagenesis of the integrase-LEDGF/p75 interface uncouples a strict correlation between in vitro protein binding and HIV-1 fitness Virology 357, 79-90 (Pubitemid 44820337)
38. Hombrouck, A., De Rijck, J., Hendrix, J., Vandekerckhove, L., Voet, A., Maeyer, M. D., Witvrouw, M., Engelborghs, Y., Christ, F., Gijsbers, R., and Debyser, Z. (2007) Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV PLoS Pathog. 3, 418-430
39. Hayouka, Z., Rosenbluh, J., Levin, A., Loya, S., Lebendiker, M., Veprintsev, D., Kotler, M., Hizi, A., Loyter, A., and Friedler, A. (2007) Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium Proc. Natl. Acad. Sci. U. S. A. 104, 8316-8321 (Pubitemid 47175485)
40. McKee, C. J., Kessl, J. J., Shkriabai, N., Dar, M. J., Engelman, A., and Kvaratskhelia, M. (2008) Dynamic modulation of HIV-1 integrase structure and function by cellular LEDGF protein J. Biol. Chem. 283, 31802-31812
41. De Rijck, J., Vandekerckhove, L., Gijsbers, R., Hombrouck, A., Hendrix, J., Vercammen, J., Engelborghs, Y., Christ, F., and Zeger Debyser, Z. (2006) Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication J. Virol. 80, 11498-11509 (Pubitemid 44788865)
42. Vandekerckhove, L., Christ, F., Van Maele, B., De Rijck, J., Gijsbers, R., Van den Haute, C., Witvrouw, M., and Debyser, Z. (2006) Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus J. Virol. 80, 1886-1896 (Pubitemid 43228728)
43. Llano, M., Saenz, D. T., Meehan, A., Wongthida, P., Peretz, M., Walker, W. H., Teo, W., and Poeschla, E. M. (2006) An Essential Role for LEDGF/p75 in HIV Integration Science 314, 461-464 (Pubitemid 44628966)
44. Al-Mawsawi, L. Q., Christ, F., Dayama, R., Debyser, Z., and Neamati, N. (2008) Inhibitory profile of a LEDGF/p75 peptide against HIV-1 integrase: Insight into integrase-DNA complex formation and catalysis FEBS Lett. 582, 1425-1430
45. Hou, Y., McGuinness, D. E., Prongay, A. J., Feld, B., Ingravallo, P., Ogert, R. A., Lunn, C. A., and Howe, J. A. (2008) Screening for antiviral inhibitors of the HIV integrase-LEDGF/p75 interaction using the AlphaScreen luminescent proximity assay J. Biomol. Screen 13, 406-414 (Pubitemid 351793981)
46. Debyser, Z. Cellular co-factors of HIV integrase - from target identification to drug discovery. Abstr. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, 2009, abstr. 74, p 91.
47. De Luca, L., Barreca, M. L., Ferro, S., Christ, F., Iraci, N., Gitto, R., Monforte, A. M., Debyser, Z., and Chimirri, A. (2009) Pharmacophore-based discovery of small-molecule inhibitors of protein-protein interactions between HIV-1 integrase and cellular cofactor LEDGF/p75 ChemMedChem 4, 1311-1316
48. Tsiang, M., Jones, G. S., Hung, M., Mukund, S., Han, B., Liu, X., Babaoglu, K., Lansdon, E., Chen, X., Todd, J., Cai, T., Pagratis, N., Sakowicz, R., and Geleziunas, R. (2009) Affinities between the binding partners of the HIV-1 integrase dimer/ lens epithelium derived growth factor (IN dimer/LEDGF) complex J. Biol. Chem. 284, 33580-33599
49. Christ, F., Voet, A., Marchand, A., Nicolet, S., Desimmie, B. A., Marchand, D., Bardiot, D., Van der Veken, N. J., Van Remoortel, B., Strelkov, S. V., De Maeyer, M., Chaltin, P., and Debyser, Z. (2010) Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication Nat. Chem. Biol. 6, 442-448
50. Bischerour, J., Leh, H., Deprez, E., Brochon, J.-C., and Mouscadet, J.-F. (2003) Disulfide-linked integrase oligomers involving C280 residues are formed in vitro and in vivo but are not essential for human immunodeficiency virus replication J. Virol. 77, 135-141 (Pubitemid 36004953)
51. Zhu, K., Dobard, C., and Chow, S. A. (2004) Requirement for integrase during reverse transcription of human immunodeficiency virus type 1 and the effect of cysteine mutations of integrase on its interactions with reverse transcriptase J. Virol. 78, 5045-5055 (Pubitemid 38581456)
52. Divita, G., Restle, T., and Goody, R. S. (1993) Characterization of the dimerization process of HIV-1 reverse transcriptase heterodimer using intrinsic protein fluorescence FEBS Lett. 324, 153-158 (Pubitemid 23170405)
53. Molteni, V., Greenwald, J., Rhodes, D., Hwang, Y., Kwiatkowski, W., Bushman, F. D., Siegel, J. S., and Choe, S. (2001) Identification of a small-molecule binding site at the dimer interface of the HIV integrase catalytic domain Acta Crystallogr. D57, 536-544 (Pubitemid 32296029)
54. Faure, A., Calmels, C., Desjobert, C., Castroviejo, M., Caumont-Sarcos, A., Tarrago-Litvak, L., Litvak, S., and Parissi, V. (2005) HIV-1 integrase crosslinked oligomers are active in vitro Nucleic Acids Res. 33, 977-986 (Pubitemid 41430518)
55. Li, M., Mizuuchi, M., Burke, T. R., Jr., and Craigie, R. (2006) Retroviral DNA integration: reaction pathway and critical intermediates EMBO J. 25, 1295-1304
56. Li, M. and Craigie, R. (2005) Processing of viral DNA ends channels the HIV-1 integration reaction to concerted integration J. Biol. Chem. 280, 29334-29339 (Pubitemid 41161388)
57. Guiot, E., Carayon, K., Delelis, O., Simon, F., Tauc, P., Zubin, E., Gottikh, M., Mouscadet, J. F., Brochon, J. C., and Deprez, E. (2006) Relationship between the oligomeric status of HIV-1 integrase on DNA enzymatic activity J. Biol. Chem. 281, 22707-22719
58. Yu, F., Jones, G. S., Hung, M., Wagner, A. H., Macarthur, H. L., Liu, X., Leavitt, S., McDermott, M. J., and Tsiang, M. (2007) HIV-1 integrase preassembled on donor DNA is refractory to activity stimulation by LEDGF/p75 Biochemistry 46, 2899-2908 (Pubitemid 46417928)
59. Lesbats, P., Metifiot, M., Calmels, C., Baranova, S., Nevinsky, G., Andreola, M. L., and Parissi, V. (2008) In vitro initial attachment of HIV-1 integrase to viral ends: control of the DNA specific interaction by the oligomerization state Nucleic Acids Res. 36, 7043-7058
60. Valkov, E., Gupta, S. S., Hare, S., Helander, A., Roversi, P., McClure, M., and Cherepanov, P. (2009) Functional and structural characterization of the integrase from the prototype foamy virus Nucleic Acids Res. 37, 243-255
61. Sinha, S. and Grandgenett, D. P. (2005) Recombinant human immunodeficiency virus type 1 integrase exhibits a capacity for full-site integration in vitro that is comparable to that of purified preintegration complexes from virus-infected cells J. Virol. 79, 8208-8216 (Pubitemid 40853524)
62. Kessl, J. J., Eidahl, J. O., Shkriabai, N., Zhao, Z., McKee, C. J., Hess, S., Burke, T. R., Jr., and Kvaratskhelia, M. (2009) An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule Mol. Pharmacol. 76, 824-832
63. Hayouka, Z., Levin, A., Maes, M., Hadas, E., Shalev, D. E., Volsky, D. J., Loyter, A., and Friedler, A. (2010) Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370 Biochem. Biophys. Res. Commun. 394, 260-265