Granulysin crystal structure and a structure-derived lytic mechanism

Daniel H. Anderson*, Michael R. Sawaya, Duilio Cascio, William Ernst, Robert Modlin, Alan Krensky, David Eisenberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

Our crystal structure of granulysin suggests a mechanism for lysis of bacterial membranes by granulysin, a 74-residue basic protein from human cytolytic T lymphocyte and natural killer cells. We determined the initial crystal structure of selenomethionyl granulysin by MAD phasing at 2 Å resolution. We present the structure model refined using native diffraction data to 0.96 Å resolution. The five-helical bundle of granulysin resembles other "saposin folds" (such as NK-lysin). Positive charges distribute in a ring around the granulysin molecule, and one face has net positive charge. Sulfate ions bind near the segment of the molecule identified as most membrane-lytic and of highest hydrophobic moment. The ion locations may indicate granulysin's orientation of initial approach towards the membrane. The crystal packing reveals one way to pack a sheet of granulysin molecules at the cell surface for a concerted lysis effort. The energy of binding granulysin charges to the bacterial membrane could drive the subsequent lytic processes. The loosely packed core facilitates a hinge or scissors motion towards exposure of hydrophobic surface that we propose tunnels the granulysin into the fracturing target membrane.

Original languageEnglish (US)
Pages (from-to)355-365
Number of pages11
JournalJournal of Molecular Biology
Volume325
Issue number2
DOIs
StatePublished - 2003

Keywords

  • Antimicrobial protein
  • Crystal structure
  • Granulysin
  • Lytic mechanism
  • Saposin fold

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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