Τίτλος:
Prothymosin α immunoactive carboxyl-terminal peptide TKKQKTDEDD stimulates lymphocyte reactions, induces dendritic cell maturation and adopts a β-sheet conformation in a sequence-specific manner
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Prothymosin α (ProTα) is a small acidic polypeptide with important immunostimulatory properties, which we have previously shown to be exerted by its carboxyl (C)-terminus. It exerts immunoenhancing effects through stimulation of monocytes via toll-like receptor (TLR) triggering. Here, we assayed the activity of synthetic peptides homologous to ProTα's C-terminus to stimulate lymphocyte functions, in particular natural killer cell cytotoxicity of peripheral blood mononuclear cells isolated from healthy donors. A synthetic decapeptide TKKQKTDEDD was identified as the most potent lymphocyte stimulator. The activity of this peptide was sequence-specific and comparable to that of the intact molecule, suggesting that ProTα's immunoactive segment encompasses the nuclear localization signal sequence of the polypeptide. Because ProTα stimulates immune responses in a monocyte-dependent manner, we further investigated whether the entire molecule and its peptide TKKQKTDEDD specifically act on monocytes and show that both can promote maturation of monocyte-derived dendritic cells (DC). Finally, knowing that, under specific conditions, ProTα forms amyloid fibrils, we studied the amyloidogenic properties of its C-terminal peptide segments, utilizing ATR FT-IR spectroscopy and transmission electron microscopy (negative staining). Although the peptide TKKQKTDEDD adopts an antiparallel β-sheet conformation under various conditions, it does not form amyloid fibrils; rather it aggregates in globular particles. These data, in conjunction with reports showing that the peptide TKKQKTDEDD is generated in vivo upon caspase-cleavage of ProTα during apoptosis, strengthen our hypothesis that immune response stimulation by ProTα is in principle exerted via its bioactive C-terminal decapaptide, which can acquire a sequence-specific β-sheet conformation and induce DC maturation. © 2008 Elsevier Ltd. All rights reserved.
Συγγραφείς:
Skopeliti, M.
Iconomidou, V.A.
Derhovanessian, E.
Pawelec, G.
Voelter, W.
Kalbacher, H.
Hamodrakas, S.J.
Tsitsilonis, O.E.
Περιοδικό:
Cellular and Molecular Immunology
Λέξεις-κλειδιά:
amyloid; caspase; polypeptide; prothymosin alpha; prothymosin alpha[100-109]; synthetic peptide; threonyllysyllysylglutaminyllysylthreonylaspartylglutamylaspartylaspartic acid; unclassified drug, amino acid sequence; apoptosis; article; beta sheet; blood donor; carboxy terminal sequence; cell function; cell isolation; cell maturation; controlled study; cytotoxicity; dendritic cell; human; human cell; immune response; immunoreactivity; in vivo study; infrared spectroscopy; long terminal repeat; lymphocyte; lymphocyte activation; lymphocyte function; monocyte; natural killer cell; normal human; nuclear localization signal; peripheral blood mononuclear cell; priority journal; protein analysis; protein cleavage; protein conformation; protein synthesis; sequence analysis; sequence homology; transmission electron microscopy, Amyloid; Apoptosis; Caspases; Cells, Cultured; Dendritic Cells; Humans; Lymphocytes; Monocytes; Peptides; Protein Precursors; Protein Structure, Secondary; Thymosin; Toll-Like Receptors
DOI:
10.1016/j.molimm.2008.09.014
