THE STRUCTURE AND FUNCTION OF STREPTOLYSIN O
Julian J. Adams,a Susanne C. Feil,a Rodney K.
Twetenb and Michael W. Parkera
aBiota Structural Biology Laboratory, St Vincent's
Institute of Medical Research
Fitzroy, Victoria 3065, Australia; bDepartment of
Microbiology and Immunology, The University of Oklahoma Health Sciences Center,
Oklahoma City, Oklahoma 73190, USA (jjadams@medstv.unimelb.edu.au)
Streptolysin O (SLO) is a
cholesterol dependant cytotoxin (CDC) secreted by Streptococcus pyrogenes. SLO is one of the key
virulence factors in streptococcus infections of soft tissue e.g.
strep throat, impetigo and necrotising fascitis. SLO is also a causative agent
in toxigenic or immunopathological disease e.g. Scarlet fever, toxic shock
syndrome and rheumatic fever. SLO is the archetype for the CDC super family of
pore forming toxins (Palmer M. (2001) The family of thiol-activated,
cholesterol-binding cytolysins. Toxicon. 39, 1681-1689), it however differs
from the other members of the family as it possesses a 70-75 amino acid
N-terminal extension, the function of this extension is unknown. There is some
evidence to suggest this difference may have a significant influence on
membrane specificity and activity. We hope to be able to shed some light on the
function and biological relevance of the N-terminal domain. Our group solved
the first structure of the CDC super family: perfringolysin O (PFO) (Rossjohn
et al. (1997) Structure of a cholesterol-binding thiol-activated cytolysin and
a model of its membrane form. Cell. 89, 685-692). This structure revealed
aspects of CDC toxin activity but much more needs to be learned. A structure of
another CDC super family member will be invaluable. The results from this
project will be used for in silico compound screening and possible
development of treatments for streptococcus infections.
As SLO has approximately 58% sequence identity with PFO it is anticipated that the structure will be amenable to solution by molecular replacement (MR). If MR from the data recently collected in house and at the APS fails to yield a structure, heavy atom soaks and multiple anomalous dispersion techniques will be employed. To this end Pt and Hg derivative crystals have being prepared and data sets collected.