Crystal Structure of an HIV Assembly and Maturation Switch

Overview

Journal Elife

Specialty Biology

Date 2016 Jul 15

PMID 27416583

Citations 84

Authors

Jonathan M Wagner

Kaneil K Zadrozny

Jakub Chrustowicz

Michael D Purdy

Mark Yeager

Barbie K Ganser-Pornillos

Owen Pornillos

Affiliations

Soon will be listed here.

Abstract

Virus assembly and maturation proceed through the programmed operation of molecular switches, which trigger both local and global structural rearrangements to produce infectious particles. HIV-1 contains an assembly and maturation switch that spans the C-terminal domain (CTD) of the capsid (CA) region and the first spacer peptide (SP1) of the precursor structural protein, Gag. The crystal structure of the CTD-SP1 Gag fragment is a goblet-shaped hexamer in which the cup comprises the CTD and an ensuing type II β-turn, and the stem comprises a 6-helix bundle. The β-turn is critical for immature virus assembly and the 6-helix bundle regulates proteolysis during maturation. This bipartite character explains why the SP1 spacer is a critical element of HIV-1 Gag but is not a universal property of retroviruses. Our results also indicate that HIV-1 maturation inhibitors suppress unfolding of the CA-SP1 junction and thereby delay access of the viral protease to its substrate.

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References

Worthylake D, Wang H, Yoo S, Sundquist W, Hill C . Structures of the HIV-1 capsid protein dimerization domain at 2.6 A resolution. Acta Crystallogr D Biol Crystallogr. 1999; 55(Pt 1):85-92. DOI: 10.1107/S0907444998007689. View

Gross I, Hohenberg H, Wilk T, Wiegers K, Grattinger M, Muller B . A conformational switch controlling HIV-1 morphogenesis. EMBO J. 2000; 19(1):103-13. PMC: 1171782. DOI: 10.1093/emboj/19.1.103. View

Accola M, Strack B, Gottlinger H . Efficient particle production by minimal Gag constructs which retain the carboxy-terminal domain of human immunodeficiency virus type 1 capsid-p2 and a late assembly domain. J Virol. 2000; 74(12):5395-402. PMC: 112023. DOI: 10.1128/jvi.74.12.5395-5402.2000. View

Amarasinghe G, De Guzman R, Turner R, Chancellor K, Wu Z, Summers M . NMR structure of the HIV-1 nucleocapsid protein bound to stem-loop SL2 of the psi-RNA packaging signal. Implications for genome recognition. J Mol Biol. 2000; 301(2):491-511. DOI: 10.1006/jmbi.2000.3979. View

Nalivaika E, Schiffer C . How does a symmetric dimer recognize an asymmetric substrate? A substrate complex of HIV-1 protease. J Mol Biol. 2000; 301(5):1207-20. DOI: 10.1006/jmbi.2000.4018. View

Tang C, Ndassa Y, Summers M . Structure of the N-terminal 283-residue fragment of the immature HIV-1 Gag polyprotein. Nat Struct Biol. 2002; 9(7):537-43. DOI: 10.1038/nsb806. View

Liang C, Hu J, Russell R, Roldan A, Kleiman L, Wainberg M . Characterization of a putative alpha-helix across the capsid-SP1 boundary that is critical for the multimerization of human immunodeficiency virus type 1 gag. J Virol. 2002; 76(22):11729-37. PMC: 136778. DOI: 10.1128/jvi.76.22.11729-11737.2002. View

Liang C, Hu J, Whitney J, Kleiman L, Wainberg M . A structurally disordered region at the C terminus of capsid plays essential roles in multimerization and membrane binding of the gag protein of human immunodeficiency virus type 1. J Virol. 2003; 77(3):1772-83. PMC: 140948. DOI: 10.1128/jvi.77.3.1772-1783.2003. View

von Schwedler U, Stray K, Garrus J, Sundquist W . Functional surfaces of the human immunodeficiency virus type 1 capsid protein. J Virol. 2003; 77(9):5439-50. PMC: 153941. DOI: 10.1128/jvi.77.9.5439-5450.2003. View

10.

Kuiken C, Korber B, Shafer R . HIV sequence databases. AIDS Rev. 2003; 5(1):52-61. PMC: 2613779. View

11.

Ma Y, Vogt V . Nucleic acid binding-induced Gag dimerization in the assembly of Rous sarcoma virus particles in vitro. J Virol. 2003; 78(1):52-60. PMC: 303394. DOI: 10.1128/jvi.78.1.52-60.2004. View

12.

Zhou J, Chen C, Aiken C . The sequence of the CA-SP1 junction accounts for the differential sensitivity of HIV-1 and SIV to the small molecule maturation inhibitor 3-O-{3',3'-dimethylsuccinyl}-betulinic acid. Retrovirology. 2004; 1:15. PMC: 479704. DOI: 10.1186/1742-4690-1-15. View

13.

Newman J, Butcher E, Patel D, Mikhaylenko Y, Summers M . Flexibility in the P2 domain of the HIV-1 Gag polyprotein. Protein Sci. 2004; 13(8):2101-7. PMC: 2279828. DOI: 10.1110/ps.04614804. View

14.

Melamed D, Mark-Danieli M, Kenan-Eichler M, Kraus O, Castiel A, Laham N . The conserved carboxy terminus of the capsid domain of human immunodeficiency virus type 1 gag protein is important for virion assembly and release. J Virol. 2004; 78(18):9675-88. PMC: 514996. DOI: 10.1128/JVI.78.18.9675-9688.2004. View

15.

DSouza V, Summers M . Structural basis for packaging the dimeric genome of Moloney murine leukaemia virus. Nature. 2004; 431(7008):586-90. DOI: 10.1038/nature02944. View

16.

Guo X, Roldan A, Hu J, Wainberg M, Liang C . Mutation of the SP1 sequence impairs both multimerization and membrane-binding activities of human immunodeficiency virus type 1 Gag. J Virol. 2005; 79(3):1803-12. PMC: 544129. DOI: 10.1128/JVI.79.3.1803-1812.2005. View

17.

Morellet N, Druillennec S, Lenoir C, Bouaziz S, Roques B . Helical structure determined by NMR of the HIV-1 (345-392)Gag sequence, surrounding p2: implications for particle assembly and RNA packaging. Protein Sci. 2005; 14(2):375-86. PMC: 2253411. DOI: 10.1110/ps.041087605. View

18.

Sakalian M, McMurtrey C, Deeg F, Maloy C, Li F, Wild C . 3-O-(3',3'-dimethysuccinyl) betulinic acid inhibits maturation of the human immunodeficiency virus type 1 Gag precursor assembled in vitro. J Virol. 2006; 80(12):5716-22. PMC: 1472563. DOI: 10.1128/JVI.02743-05. View

19.

Li F, Zoumplis D, Matallana C, Kilgore N, Reddick M, Yunus A . Determinants of activity of the HIV-1 maturation inhibitor PA-457. Virology. 2006; 356(1-2):217-24. DOI: 10.1016/j.virol.2006.07.023. View

20.

Adamson C, Ablan S, Boeras I, Goila-Gaur R, Soheilian F, Nagashima K . In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). J Virol. 2006; 80(22):10957-71. PMC: 1642185. DOI: 10.1128/JVI.01369-06. View