Self-interaction of pneumolysin, the pore-forming protein toxin of Streptococcus pneumoniae

The pathogenically important cholesterol-binding pore-forming bacterial "th iol-activated" toxins (TATs) are commonly believed to be monomeric in solut ion and to undergo a transition on membrane binding mediated by cholesterol to an oligomeric pore. We present evidence, gained through the application of a number of biochemical and biophysical techniques with associated mode lling, that the TAT from Streptococcus pneumoniae, pneumolysin, is in fact able to self-associate in solution to form the same oligomeric structures. The weak interaction leading to solution oligomerization is manifested at l ow concentrations in a dimeric toxin form. The inhibition of toxin self-int eraction by derivatization of the single cysteine residue in pneumolysin wi th the thiol-active agent dithio(bis)nitrobenzoic acid indicates that self- interaction is mediated by the fourth domain of the protein, which has a fo ld similar to other proteins known to self-associate. This interaction is t hought to have implications for the understanding of mechanisms of pore for mation and complement activation by pneumolysin. (C) 1998 Academic Press.