The human-specific action of intermedilysin, a homolog of streptolysin O, is dictated by domain 4 of the protein

Hideaki Nagamune*, Kazuto Ohkura, Akiko Sukeno, Graeme Cowan, Timothy J. Mitchell, Wataru Ito, Ooki Ohnishi, Kanako Hattori, Miki Yamato, Katsuhiko Hirota, Yoichiro Miyake, Takuya Maeda, Hiroki Kourai

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Intermedilysin is a pore-forming cytolysin belonging to the streptolysin O gene family known as the 'Cholesterol-binding/dependent cytolysins' and is unique within the family in that it is highly human-specific. TMs specificity suggests interaction with a component of human cells other than cholesterol, the proposed receptor for the other toxins of the gene family. Indeed, intermedilysin showed no significant degree of affinity to free or liposome-embedded cholesterol. Characterization of intermedilysin undecapeptide mutants revealed that this lack of affinity to cholesterol was a result of the substitutions of intermedilysin in this region. Absorption assays with erythrocyte membranes from various animals, competitive inhibition with domain 4 of intermedilysin and liposome-binding assays of streptolysin O and intermedilysin indicated that cell membrane binding is the human-specific step of intermedilysin action, that the host cell membrane-binding site is located within domain 4 in common with other members of the family and that the receptor for this toxin is not cholesterol. The species specificity of undecapeptide mutants of intermedilysin and streptolysin O and chimeric mutants between intermedilysin and streptolysin O, and intermedilysin and pneumolysin indicated that domain 4 of intermedilysin determines the human-specific action step and the cell-binding site of domain 4 lies within the 56 amino acids of the C-terminal, excluding the undecapeptide region.

Original languageEnglish
Pages (from-to)677-692
Number of pages16
JournalMicrobiology and Immunology
Volume48
Issue number9
DOIs
Publication statusPublished - 1 Jan 2004

Keywords

  • Hemolysin
  • Human-specific
  • Intermedilysin
  • Pore-forming toxin

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