Correlation of the conformation of a modified ribonuclease octapeptide, homologous to peptide T, with its ability to induce CD4-dependent monocyte chemotaxis.
Peptide T, from the human immunodeficiency virus (HIV), whose sequence is Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr, has been shown to inhibit attachment of this virus to T cells and neural cells bearing the CD4 receptor. This peptide shares extensive homology with the 19-26 segment of ribonuclease A (RNase A), whose sequence is Ala-Ala-Ser-Ser-Ser-Asn-Tyr-Cys. Based on comparison of the structures of peptides occurring in proteins of known structure that are homologous to peptide T, viz, RNase A and endothiapepsin and on conformational energy calculations, we predicted that peptide T adopts a structure much like that for residues 19-26 in RNase A. A critical feature is a bend involving residues Thr 4-Asn 7 in peptide T corresponding to Ser 22-Tyr 25 in the RNase A peptide. Our proposed structure for peptide T has recently been confirmed by Cotelle et al. (Biochem. Biophys. Res. Commun. 171, 596-602). We now show directly that the RNase A peptide, with Met replacing Cys 26 to prevent disulfide exchange reactions, strongly induces monocyte-chemotaxis that is blocked by anti-CD4 monoclonal antibody. Both peptide T and RNase A fail to induce chemotaxis, however, in neutrophils which do not express surface CD4 receptors. These results suggest that both peptides interact with the CD4 receptor in inducing monocyte chemotaxis. We have also prepared cyclo-RNase A peptide with Met 26. Using molecular dynamics and conformational energy calculations, we find that the cyclic peptide cannot form a bend structure involving Ser 22-Tyr 25 that is superimposable on the RNase A bend.(ABSTRACT TRUNCATED AT 250 WORDS)
Licht
D
D
Heterocycle Research Corp, New City, New York 10956.
Cronstein
B
B
Dykes
D C
DC
Pedersen
J
J
Luster
S M
SM
Trampota
M
M
Hull
E
E
Friedman
F K
FK
Pincus
M R
MR
D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003500:Cyclization; D006678:HIV / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D009000:Monocytes / Q000502:physiology*; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D015717:Peptide T / Q000737:chemistry*; D011487:Protein Conformation; D012259:Ribonuclease, Pancreatic / Q000737:chemistry* / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid
D015704:CD4 Antigens; D009842:Oligopeptides; D015717:Peptide T; D012259:Ribonuclease, Pancreatic