title: Complete dissociation of the HIV-1 gp41 ectodomain and membrane proximal regions upon phospholipid binding.
abstract: The envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. Strong lipid affinity of the ectodomain suggests that its heptad repeat regions play an active role in destabilizing membranes by directly binding to the lipid bilayers and thereby lowering the free-energy barrier for membrane fusion. In such a model, immediately following the shedding of gp120, the N-heptad and C-heptad helices dissociate and melt into the host cell and viral membranes, respectively, pulling the destabilized membranes into juxtaposition, ready for fusion. Post-fusion, reaching the final 6-helix bundle (6 HB) conformation then involves competition between intermolecular interactions needed for formation of the symmetric 6 HB trimer and the membrane affinity of gp41's ectodomain, including its membrane-proximal regions. Our solution NMR study of the structural and dynamic properties of three constructs containing the ectodomain of gp41 with and without its membrane-proximal regions suggests that these segments do not form inter-helical interactions until the very late steps of the fusion process. Interactions between the polar termini of the heptad regions, which are not associating with the lipid surface, therefore may constitute the main driving force initiating formation of the final post-fusion states. The absence of significant intermolecular ectodomain interactions in the presence of dodecyl phosphocholine highlights the importance of trimerization of gp41's transmembrane helix to prevent complete dissociation of the trimer during the course of fusion.
authors: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA.
authors: Julien
authors: J
authors: Roche
authors: John M
authors: JM
authors: Louis
authors: Annie
authors: A
authors: Aniana
authors: Rodolfo
authors: R
authors: Ghirlando
authors: Ad
authors: A
authors: Bax
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism; D008561:Membrane Fusion / Q000502:physiology*; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D010743:Phospholipids / Q000378:metabolism*; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D008051:Lipid Bilayers; D010743:Phospholipids; C514793:gp120 protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1; D010767:Phosphorylcholine; C028810:dodecylphosphocholine
references: Structure. 2014 Sep 2;22(9):1225-6
references: 25185826
references: Biochim Biophys Acta. 2009 Sep;1788(9):1804-12
references: 19540828
references: Biochim Biophys Acta. 2015 Jan;1848(1 Pt B):289-98
references: 25078440
references: Biochemistry. 2000 Jan 25;39(3):496-507
references: 10642174
references: J Mol Biol. 2000 Feb 25;296(3):911-9
references: 10677291
references: J Mol Biol. 2000 Aug 25;301(4):905-14
references: 10966795
references: Annu Rev Biochem. 2000;69:531-69
references: 10966468
references: J Virol. 2001 Mar;75(6):3038-42
references: 11222732
references: Biochemistry. 2002 Apr 9;41(14):4678-85
references: 11926830
references: Mol Biol Cell. 2003 Mar;14(3):926-38
references: 12631714
references: Biochim Biophys Acta. 2003 Jul 11;1614(1):36-50
references: 12873764
references: Science. 1994 Oct 14;266(5183):234-6
references: 7939658
references: Science. 1994 Oct 14;266(5183):274-6
references: 7939662
references: Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12205-9
references: 8618870
references: J Biol Chem. 1996 Jun 7;271(23):13417-21
references: 8662770
references: Science. 1997 Apr 4;276(5309):131-3
references: 9082985
references: Cell. 1997 Apr 18;89(2):263-73
references: 9108481
references: Nature. 1997 May 22;387(6631):426-30
references: 9163431
references: Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12303-8
references: 9356444
references: Nat Struct Biol. 1998 Apr;5(4):276-9
references: 9546217
references: EMBO J. 1998 Aug 17;17(16):4572-84
references: 9707417
references: Eur Biophys J. 2011 Apr;40(4):489-502
references: 21222118
references: J Am Chem Soc. 2011 Sep 14;133(36):14184-7
references: 21848255
references: Biochemistry. 2012 Apr 3;51(13):2867-78
references: 22413880
references: J Biomol NMR. 2012 Jul;53(3):209-21
references: 22689066
references: Biochemistry. 2012 Jun 19;51(24):4779-89
references: 22650985
references: J Biol Chem. 2012 Nov 30;287(49):40841-9
references: 23043104
references: J Biol Chem. 2013 Jan 4;288(1):234-46
references: 23184960
references: Angew Chem Int Ed Engl. 2013 Apr 2;52(14):3911-5
references: 23450638
references: PLoS One. 2013;8(4):e60302
references: 23565220
references: Curr Opin Struct Biol. 2013 Apr;23(2):268-76
references: 23602427
references: Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12438-43
references: 23757493
references: Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):E4175-7
references: 24106301
references: Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):E4172-4
references: 24106302
references: Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18037-41
references: 24106306
references: Nat Struct Mol Biol. 2013 Dec;20(12):1352-7
references: 24154805
references: J Biol Chem. 2013 Dec 13;288(50):35726-35
references: 24178297
references: Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):E4178-82
references: 24350339
references: Science. 2013 Dec 20;342(6165):1477-83
references: 24179159
references: Science. 2013 Dec 20;342(6165):1484-90
references: 24179160
references: Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1391-6
references: 24474763
references: J Mol Biol. 2014 Mar 6;426(5):1077-94
references: 24246500
references: Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3425-30
references: 24550514
references: Curr Opin Virol. 2014 Feb;4:1-7
references: 24525288
references: Structure. 2014 Sep 2;22(9):1311-21
references: 25132083
references: J Mol Biol. 1999 Feb 19;286(2):489-503
references: 9973566
references: Biochemistry. 2005 Dec 13;44(49):16167-80
references: 16331977
references: J Virol. 2006 Apr;80(7):3249-58
references: 16537592
references: J Mol Biol. 2006 Dec 15;364(5):1103-17
references: 17045292
references: Biochemistry. 2009 Mar 31;48(12):2714-22
references: 19222185
references: J Biol Chem. 2010 May 7;285(19):14681-8
references: 20197275
references: PLoS Pathog. 2010 May;6(5):e1000880
references: 20463810
references: Biochemistry. 2014 Nov 25;53(46):7184-98
references: 25372604
references: Curr Opin Struct Biol. 2007 Apr;17(2):244-52
references: 17395457
references: Nat Struct Mol Biol. 2008 Jul;15(7):690-8
references: 18596815
references: Biochemistry. 2009 Apr 14;48(14):3166-75
references: 19206186
references: Retrovirology. 2010;7:95
references: 21073746