Characterization of an amphiphilic helical structure in β-endorphin through the design, synthesis, and study of model peptides

J. W. Taylor, R. J. Miller, E. T. Kaiser

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

We have proposed that the biological properties of β-endorphin are determined by the combination of a highly specific opiate-receptor recognition sequence, residues 1-5, at the NH2terminus and a potential amphiphilic α- or π-helix in the COOH-terminal residues 13-29, connected via a hydrophilic peptide link. In the α-form, the amphiphilic helix has a hydrophobic domain which twists around the helix and covers approximately half of its surface. Other prominent features of the helix are its basicity and the 2 aromatic residues Phe 18 and Tyr 27. Peptide 3 was synthesized and studied to determine how the properties of β-endorphin depend on the general characteristics of the amphiphilic α-helical region. Residues 1-13 of peptide 3 and β-endorphin are homologous. In contrast, residues 14-31 of peptide 3 were chosen to be almost nonhomologous to those or β-endorphin, while having a high helix-forming potential. Indeed, peptide 3 can form an amphiphilic helix in its COOH-terminal region that is similar in the shape of its hydrophobic domain to the helix described for β-endorphin. Peptide 3 had considerable helical structure in aqueous 2,2,2-trifluoroethanol solutions, as does β-endorphin, and had much higher affinities for δ- and μ-opiate receptors than β-endorphin, while it retained the same δ/μ selectivity. Peptide 3 also had a greater resistance to proteolysis in rat brain homogenates than β-endorphin, and a higher opiate activity on the guinea pig ileum. In opiate assays on the rat vas deferens, which are very specific for β-endorphin, peptide 3 retained a high activity (IC50 = 267 ± 48 nM) although it was less active than β-endorphin (IC50 = 41 ± 2 nM). Most important, peptide 3 displayed a potent opiate analgesic effect which lasted considerably longer than that of β-endorphin, when equal doses of the peptides were injected intracerebrally into mice. These results strongly suggest that an amphiphilic helical structure in β-endorphin residues 13-29 contributes to opiate-receptor interactions and determines the resistance to proteolysis of the whole molecule. A comparison of these properties with those of other model peptides shows that the shape of the hydrophobic domain in this helix prevents self-association and nonspecific tissue binding of β-endorphin, that the positive charge in this structure enhances δ- and μ-receptor binding, and that activities on the rat vas deferens and in analgesic assays may have different additional specificities for the aromatic residues on the helix surface.

Original languageEnglish (US)
Pages (from-to)4464-4471
Number of pages8
JournalJournal of Biological Chemistry
Volume258
Issue number7
StatePublished - Jan 1 1983

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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