Hydrophobic substitutions in the first residue of the CRAC segment of the gp41 protein of HIV.
We investigated the peptides N-acetyl-AWYIK-amide and N-acetyl-VWYIK-amide corresponding to single amino acid substitutions in LWYIK, a segment found in the gp41 protein of HIV and believed to play a role in sequestering this protein to a cholesterol-rich domain in the membrane. The effects of these peptides on the thermotropic phase transitions of 1-stearoyl-2-oleoylphosphatidylcholine (SOPC) and mixtures of SOPC and cholesterol were intermediate between that having the wild-type sequence (LWYIK) and another (IWYIK), the least active peptide previously studied. This correlated with results from studies of single mutations in the gp41 protein of HIV-1, in which L679 of the LWYIK segment is replaced with either A or V, measuring the capability of TZM-BL HeLa-based HIV-1 indicator cells to form syncytia. The peptides were also comparatively analyzed in silico. All together, the results suggest that the mode of interaction of this region of gp41 with the polar heads of membrane lipids contributes to its cholesterol selectivity and that this is somehow related to the biological activity of the viral glycoprotein.
Vishwanathan
Sundaram A
SA
Emory Vaccine Research Center, Yerkes, Emory University, 954 Gatewood Rd, Atlanta, Georgia 30329, USA.
Thomas
Annick
A
Brasseur
Robert
R
Epand
Raquel F
RF
Hunter
Eric
E
Epand
Richard M
RM
D000595:Amino Acid Sequence; D002152:Calorimetry, Differential Scanning; D002459:Cell Fusion; D002460:Cell Line; D002784:Cholesterol / Q000737:chemistry; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D016296:Mutagenesis; D009154:Mutation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry; D011485:Protein Binding
D015700:HIV Envelope Protein gp41; D008565:Membrane Proteins; D009842:Oligopeptides; D010713:Phosphatidylcholines; C027891:1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine; D002784:Cholesterol