Membrane interactions of the synthetic N-terminal peptide of HIV-1 gp41 and its structural analogs.
Structural and functional studies assessed the membrane actions of the N terminus of HIV-1 glycoprotein 41000 (gp41). Earlier site-directed mutagenesis has shown that key amino acid changes in this gp41 domain inhibit viral infection and syncytia formation. Here, a synthetic peptide corresponding to the N terminus of gp41 (FP; 23 residues, 519-541), and also FP analogs (FP520V/E with Val-->Glu at residue 520; FP527L/R with Leu-->Arg at 527; FP529F/Y with Phe-->Tyr at 529; and FPCLP1 with FP truncated at 525) incorporating these modifications were prepared. When added to human erythrocytes at physiologic pH, the lytic and aggregating activities of the FP analogs were much reduced over those with the wild-type FP. With resealed human erythrocyte ghosts, the lipid-mixing activities of the FP analogs were also substantially depressed over that with the wild-type FP. Combined with results from earlier studies, theoretical calculations using hydrophobic moment plot analysis and physical experiments using circular dichroism and Fourier transform infrared spectroscopy indicate that the diminished lysis and fusion noted for FP analogs may be due to altered peptide-membrane lipid interactions. These data confirm that the N-terminal gp41 domain plays critical roles in the cytolysis and fusion underlying HIV-cell infection.
Mobley
P W
PW
Chemistry Department, California State Polytechnic University, Pomona, Pomona, CA, USA.
Waring
A J
AJ
Sherman
M A
MA
Gordon
L M
LM
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D002462:Cell Membrane / Q000737:chemistry*; D002942:Circular Dichroism; D004910:Erythrocyte Membrane / Q000737:chemistry; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D015497:HIV-1; D006801:Humans; D008081:Liposomes; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
D000596:Amino Acids; D015700:HIV Envelope Protein gp41; D008081:Liposomes; D010446:Peptide Fragments; C076451:HIV envelope protein gp41 (519-541)