title: Structural and functional properties of the membranotropic HIV-1 glycoprotein gp41 loop region are modulated by its intrinsic hydrophobic core.
abstract: The gp41 disulfide loop region switches from a soluble state to a membrane-bound state during the human immunodeficiency virus type 1 (HIV-1) envelope-mediated membrane fusion process. The loop possesses a hydrophobic core at the center of the region with an unusual basic residue (Lys-601). Furthermore, two loop core mutations, K601A and L602A, are found to inhibit HIV-1 infectivity while keeping wild type-like levels of the envelope, implying that they exert an inhibitory effect on gp41 during the membrane fusion event. Here, we investigated the mode of action of these mutations on the loop region. We show that the K601A mutation, but not the L602A mutation, abolished the binding of a loop-specific monoclonal antibody to a loop domain peptide. Additionally, the K601A, but not the L602A, impaired disulfide bond formation in the peptides. This was correlated with changes in the circular dichroism spectrum imposed by the K601A mutation. In the membrane, however, the L602A, but not the K601A, reduced the lipid mixing ability of the loop peptides, which was correlated with decreased α-helical content of the L602A mutant. The results suggest that the Lys-601 residue provides a moderate hydrophobicity level within the gp41 loop core that contributes to the proper structure and function of the loop inside and outside the membrane. Because basic residues are found between the loop Cys residues of several lentiviral fusion proteins, the findings may contribute to understanding the fusion mechanism of other viruses as well.
authors: From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100 Israel and.
authors: Jiayin
authors: J
authors: Qiu
authors: Avraham
authors: A
authors: Ashkenazi
authors: Shuwen
authors: S
authors: Liu
authors: Yechiel
authors: Y
authors: Shai
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002942:Circular Dichroism; D019295:Computational Biology; D004220:Disulfides / Q000378:metabolism; D015483:HIV Antibodies / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007477:Ions; D008055:Lipids / Q000737:chemistry; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D017433:Protein Structure, Secondary; D015302:Simian Immunodeficiency Virus / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000911:Antibodies, Monoclonal; D004220:Disulfides; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D007477:Ions; D008055:Lipids
keywords: Biophysics; HIV-1; Membrane Fusion; Membrane Proteins; Peptide Conformation; Peptide-Membrane Interaction; Viral Fusion Protein
references: J Virol. 2005 Apr;79(8):5142-52
references: 15795298
references: J Mol Biol. 2003 Mar 7;326(5):1489-501
references: 12595260
references: J Biol Chem. 2005 Jul 22;280(29):27284-8
references: 15917239
references: J Virol. 1991 Aug;65(8):4169-76
references: 2072448
references: FASEB J. 2010 Nov;24(11):4196-202
references: 20605950
references: FEBS Lett. 2003 Jun 5;544(1-3):69-73
references: 12782292
references: Nature. 1993 Sep 9;365(6442):113
references: 8371754
references: FASEB J. 2011 Jul;25(7):2156-66
references: 21429941
references: Biochim Biophys Acta. 2003 Jul 11;1614(1):36-50
references: 12873764
references: Annu Rev Biochem. 2001;70:777-810
references: 11395423
references: Biochim Biophys Acta. 2006 Jan;1758(1):111-23
references: 16483537
references: Blood. 2004 Mar 1;103(5):1586-94
references: 14592831
references: J Virol. 1991 Nov;65(11):6349-52
references: 1717722
references: J Virol. 1997 Apr;71(4):2674-84
references: 9060620
references: Proc Natl Acad Sci U S A. 1990 Jun;87(12):4650-4
references: 2191297
references: Biochemistry. 1982 Sep 28;21(20):5020-31
references: 6814482
references: J Virol. 1991 Sep;65(9):4832-8
references: 1714520
references: AIDS Res Hum Retroviruses. 1989 Aug;5(4):431-40
references: 2788443
references: Science. 1992 Nov 6;258(5084):917-24
references: 1439803
references: EMBO J. 1998 Aug 17;17(16):4572-84
references: 9707417
references: Cell. 1997 Apr 18;89(2):263-73
references: 9108481
references: J Mol Biol. 2007 Nov 16;374(1):220-30
references: 17919659
references: Biochemistry. 1981 Jul 7;20(14):4093-9
references: 7284312
references: Biochim Biophys Acta. 2001 May 31;1536(2-3):116-22
references: 11406346
references: Biochemistry. 2012 Sep 4;51(35):6981-9
references: 22894130
references: Blood. 2013 Mar 21;121(12):2244-52
references: 23325839
references: Nat Rev Immunol. 2004 Mar;4(3):199-210
references: 15039757
references: J Mol Biol. 2005 Feb 11;346(1):377-85
references: 15663952
references: Nature. 1997 May 22;387(6631):426-30
references: 9163431
references: J Virol. 2001 Jul;75(14):6635-44
references: 11413331
references: AIDS Res Hum Retroviruses. 1992 Sep;8(9):1571-80
references: 1457203
references: Nat Rev Mol Cell Biol. 2003 Apr;4(4):309-19
references: 12671653
references: Mol Cell. 2010 Mar 12;37(5):656-67
references: 20227370
references: Annu Rev Microbiol. 2002;56:521-38
references: 12142475
references: J Virol. 2004 Jan;78(2):811-20
references: 14694113
references: Biochim Biophys Acta. 2003 Jul 11;1614(1):116-21
references: 12873772
references: Biochim Biophys Acta. 2000 Jul 31;1467(1):227-43
references: 10930525