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Orientation and helical conformation of a tissue‐specific hunter‐killer peptide in micelles
Author(s) -
Plesniak Leigh A.,
Parducho Jonathan I.,
Ziebart Angie,
Geierstanger Bernhard H.,
Whiles Jennifer A.,
Melacini Guiseppe,
Jennings Patricia A.
Publication year - 2004
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.04853204
Subject(s) - peptide , biophysics , peptide sequence , microbiology and biotechnology , biology , liposome , biochemistry , chemistry , gene
Hunter‐killer peptides are chimeric synthetic peptides that selectively target specific cell types for an apoptotic death. These peptides, which are models for potential therapeutics, contain a homing sequence for receptor‐mediated interactions and a pro‐apoptotic sequence. Homing domains have been designed to target angiogenic tumor cells, prostate cells, arthritic tissue and, most recently, adipose tissue. After a receptor‐mediated internalization, the apoptotic sequence, which contains D‐enantiomer amino acids, initiates apoptosis through mitochondrial membrane disruption. We have begun structure and functional studies on a peptide (HKP1) that specifically targets angiogenic tumor cells for apoptosis. As a model for mitochondrial membrane disruption, we have examined peptide‐induced leakage of a calcein fluorophore from large unilamellar vesicles. These experiments demonstrate more potent leakage activity by HKP1 than the peptide lacking the homing domain. Circular dichroism and 2D homonuclear NMR experiments demonstrate that this tumor‐specific HKP adopts a left‐handed amphipathic helix in association with dodecylphosphorylcholine micelles in a parallel orientation to the lipid–water interface with the homing domain remaining exposed to solvent. The amphipathic helix of the apoptotic domain orients with nonpolar leucine and alanine residues inserting most deeply into the lipid environment.