HIV-1 Envelope Proteins Complete Their Folding into Six-helix Bundles Immediately After Fusion Pore Formation

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2003 Mar 13

PMID 12631714

Citations 111

Authors

Ruben M Markosyan

Fredric S Cohen

Grigory B Melikyan

Affiliations

Soon will be listed here.

Abstract

Fusion proteins of many viruses, including HIV-1 envelope protein (Env), fold into six-helix bundle structures. Fusion between individual Env-expressing cells and target cells was studied by fluorescence microscopy, and a temperature jump technique, to determine whether folding of Env into a bundle is complete by the time fusion pores have formed. Lowering temperature to 4 degrees C immediately after a pore opened halted pore growth, which quickly resumed when temperature was raised again. HIV gp41-derived peptides that inhibit bundle formation (C34 or N36) caused the cold-arrested pore to quickly and irreversibly close, demonstrating that bundle formation is not complete by the time a pore has formed. In contrast, lowering the temperature to an intermediate value also halted pore growth, but the pore was not closed by the bundle-inhibiting peptides, and it enlarged when temperature was again elevated. This latter result shows that bundle formation is definitely required for the fusion process, but surprisingly, some (if not all) bundle formation occurs after a pore has formed. It is concluded that an essential function of the bundle is to stabilize the pore against collapse and ensure its growth.

Citing Articles

HIV-1 envelope facilitates the development of protease inhibitor resistance through acquiring mutations associated with viral entry and immune escape.

Maphumulo N, Gordon M Front Microbiol. 2024; 15:1388729.

PMID: 38699474 PMC: 11063367. DOI: 10.3389/fmicb.2024.1388729.

HIV Infection: Shaping the Complex, Dynamic, and Interconnected Network of the Cytoskeleton.

Cabrera-Rodriguez R, Perez-Yanes S, Lorenzo-Sanchez I, Trujillo-Gonzalez R, Estevez-Herrera J, Garcia-Luis J Int J Mol Sci. 2023; 24(17).

PMID: 37685911 PMC: 10487602. DOI: 10.3390/ijms241713104.

Real-time Exchange of the Lipid-bound Intermediate and Post-fusion States of the HIV-1 gp41 Ectodomain.

Chiliveri S, Louis J, Best R, Bax A J Mol Biol. 2022; 434(16):167683.

PMID: 35700771 PMC: 9378563. DOI: 10.1016/j.jmb.2022.167683.

Transient lipid-bound states of spike protein heptad repeats provide insights into SARS-CoV-2 membrane fusion.

Chiliveri S, Louis J, Ghirlando R, Bax A Sci Adv. 2021; 7(41):eabk2226.

PMID: 34623907 PMC: 8500521. DOI: 10.1126/sciadv.abk2226.

The late endosome-resident lipid bis(monoacylglycero)phosphate is a cofactor for Lassa virus fusion.

Markosyan R, Marin M, Zhang Y, Cohen F, Melikyan G PLoS Pathog. 2021; 17(9):e1009488.

PMID: 34492091 PMC: 8448326. DOI: 10.1371/journal.ppat.1009488.

References

Markosyan R, Ma X, Lu M, Cohen F, Melikyan G . The mechanism of inhibition of HIV-1 env-mediated cell-cell fusion by recombinant cores of gp41 ectodomain. Virology. 2002; 302(1):174-84. DOI: 10.1006/viro.2002.1593. View

Golding H, Zaitseva M, de Rosny E, King L, Manischewitz J, Sidorov I . Dissection of human immunodeficiency virus type 1 entry with neutralizing antibodies to gp41 fusion intermediates. J Virol. 2002; 76(13):6780-90. PMC: 136262. DOI: 10.1128/jvi.76.13.6780-6790.2002. View

Dubay J, Roberts S, BRODY B, Hunter E . Mutations in the leucine zipper of the human immunodeficiency virus type 1 transmembrane glycoprotein affect fusion and infectivity. J Virol. 1992; 66(8):4748-56. PMC: 241301. DOI: 10.1128/JVI.66.8.4748-4756.1992. View

Cao J, Bergeron L, Helseth E, Thali M, Repke H, Sodroski J . Effects of amino acid changes in the extracellular domain of the human immunodeficiency virus type 1 gp41 envelope glycoprotein. J Virol. 1993; 67(5):2747-55. PMC: 237598. DOI: 10.1128/JVI.67.5.2747-2755.1993. View

Jiang S, Lin K, Strick N, Neurath A . HIV-1 inhibition by a peptide. Nature. 1993; 365(6442):113. DOI: 10.1038/365113a0. View

Wild C, Shugars D, Greenwell T, McDanal C, Matthews T . Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. Proc Natl Acad Sci U S A. 1994; 91(21):9770-4. PMC: 44898. DOI: 10.1073/pnas.91.21.9770. View

Chen C, Matthews T, McDanal C, Bolognesi D, Greenberg M . A molecular clasp in the human immunodeficiency virus (HIV) type 1 TM protein determines the anti-HIV activity of gp41 derivatives: implication for viral fusion. J Virol. 1995; 69(6):3771-7. PMC: 189094. DOI: 10.1128/JVI.69.6.3771-3777.1995. View

Chernomordik L, Kozlov M, Zimmerberg J . Lipids in biological membrane fusion. J Membr Biol. 1995; 146(1):1-14. DOI: 10.1007/BF00232676. View

Lu M, Blacklow S, Kim P . A trimeric structural domain of the HIV-1 transmembrane glycoprotein. Nat Struct Biol. 1995; 2(12):1075-82. DOI: 10.1038/nsb1295-1075. View

10.

Durrer P, Galli C, Hoenke S, Corti C, GLUCK R, Vorherr T . H+-induced membrane insertion of influenza virus hemagglutinin involves the HA2 amino-terminal fusion peptide but not the coiled coil region. J Biol Chem. 1996; 271(23):13417-21. DOI: 10.1074/jbc.271.23.13417. View

11.

Endres M, Clapham P, Marsh M, Ahuja M, Turner J, McKnight A . CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Cell. 1996; 87(4):745-56. DOI: 10.1016/s0092-8674(00)81393-8. View

12.

Hernandez L, Hoffman L, Wolfsberg T, White J . Virus-cell and cell-cell fusion. Annu Rev Cell Dev Biol. 1996; 12:627-61. DOI: 10.1146/annurev.cellbio.12.1.627. View

13.

Weissenhorn W, Dessen A, Harrison S, Skehel J, Wiley D . Atomic structure of the ectodomain from HIV-1 gp41. Nature. 1997; 387(6631):426-30. DOI: 10.1038/387426a0. View

14.

Deng H, Unutmaz D, Kewalramani V, Littman D . Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature. 1997; 388(6639):296-300. DOI: 10.1038/40894. View

15.

Durell S, Sakaguchi K, Appella E, Blumenthal R . Dilation of the human immunodeficiency virus-1 envelope glycoprotein fusion pore revealed by the inhibitory action of a synthetic peptide from gp41. J Cell Biol. 1998; 140(2):315-23. PMC: 2132584. DOI: 10.1083/jcb.140.2.315. View

16.

Chan D, Kim P . HIV entry and its inhibition. Cell. 1998; 93(5):681-4. DOI: 10.1016/s0092-8674(00)81430-0. View

17.

Poirier M, Xiao W, Macosko J, Chan C, Shin Y, Bennett M . The synaptic SNARE complex is a parallel four-stranded helical bundle. Nat Struct Biol. 1998; 5(9):765-9. DOI: 10.1038/1799. View

18.

Sutton R, Fasshauer D, Jahn R, Brunger A . Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution. Nature. 1998; 395(6700):347-53. DOI: 10.1038/26412. View

19.

Kilby J, Hopkins S, Venetta T, DiMassimo B, Cloud G, Lee J . Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med. 1998; 4(11):1302-7. DOI: 10.1038/3293. View

20.

Chan D, Chutkowski C, Kim P . Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target. Proc Natl Acad Sci U S A. 1998; 95(26):15613-7. PMC: 28092. DOI: 10.1073/pnas.95.26.15613. View