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Departments of
*
Cardiothoracic Surgery and
Pediatrics, Stanford University, Stanford, CA 94305
Granulysin, a 9-kDa protein localized to human CTL and NK cell
granules, is cytolytic against tumor cells and microbes. Molecular
modeling predicts that granulysin is composed of five 
-helices
separated by short loop regions. In this report, synthetic peptides
corresponding to the linear granulysin sequence were characterized for
lytic activity. Peptides corresponding to the central region of
granulysin lyse bacteria, human cells, and synthetic liposomes, while
peptides corresponding to the amino or carboxyl regions are not lytic.
Peptides corresponding to either helix 2 or helix 3 lyse bacteria,
while lysis of human cells and liposomes is dependent on the helix 3
sequence. Peptides in which positively charged arginine residues are
substituted with neutral glutamine exhibit reduced lysis of all three
targets. While reduction of recombinant 9-kDa granulysin increases
lysis of Jurkat cells, reduction of cysteine-containing granulysin
peptides decreases lysis of Jurkat cells. In contrast, lysis of
bacteria by recombinant granulysin or by cysteine-containing granulysin
peptides is unaffected by reducing conditions. Jurkat cells transfected
with either CrmA or Bcl-2 are protected from lysis by recombinant
granulysin or the peptides. Differential activity of granulysin
peptides against tumor cells and bacteria may be exploited to develop
specific antibiotics without toxicity for mammalian
cells.
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