The Crystal Structure of Pneumolysin at 2 0 Å Resolution Reveals the Molecular
Packing of the Pre-pore Complex
#MMPMID26333773
Marshall JE
; Faraj BH
; Gingras AR
; Lonnen R
; Sheikh MA
; El-Mezgueldi M
; Moody PC
; Andrew PW
; Wallis R
Sci Rep
2015[Sep]; 5
(?): 13293
PMID26333773
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Pneumolysin is a cholesterol-dependent cytolysin (CDC) and virulence factor of
Streptococcus pneumoniae. It kills cells by forming pores assembled from
oligomeric rings in cholesterol-containing membranes. Cryo-EM has revealed the
structures of the membrane-surface bound pre-pore and inserted-pore oligomers,
however the molecular contacts that mediate these oligomers are unknown because
high-resolution information is not available. Here we have determined the crystal
structure of full-length pneumolysin at 1.98?Å resolution. In the structure,
crystal contacts demonstrate the likely interactions that enable polymerisation
on the cell membrane and the molecular packing of the pre-pore complex. The
hemolytic activity is abrogated in mutants that disrupt these intermolecular
contacts, highlighting their importance during pore formation. An additional
crystal structure of the membrane-binding domain alone suggests that changes in
the conformation of a tryptophan rich-loop at the base of the toxin promote
monomer-monomer interactions upon membrane binding by creating new contacts.
Notably, residues at the interface are conserved in other members of the CDC
family, suggesting a common mechanism for pore and pre-pore assembly.
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