Structural Studies of Streptococcus pyogenes Streptolysin O Provide Insights into the Early Steps of Membrane Penetration
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- 作者：Susanne C. Feil ; David B. Ascher ; Michael J. Kuiper ; Rodney K. Tweten ; Michael W. Parker
- 关键词：ALO ; anthrolysin ; CDC ; cholesterol-dependent cytolysin ; ILY ; intermedilysin ; PFO ; perfringolysin O ; SLO ; streptolysin O ; SLY ; suilysin ; NHMRC ; National Health and Medical Research Council of Australia
- 刊名：Journal of Molecular Biology
- 出版年：20 February, 2014
- 年：2014
- 卷：426
- 期：4
- 页码：785-792
- 全文大小：1115 K
文摘
Cholesterol-dependent cytolysins (CDCs) are a large family of bacterial toxins that exhibit a dependence on the presence of membrane cholesterol in forming large pores in cell membranes. Significant changes in the three-dimensional structure of these toxins are necessary to convert the soluble monomeric protein into a membrane pore. We have determined the crystal structure of the archetypical member of the CDC family, streptolysin O (SLO), a virulence factor from Streptococcus pyogenes. The overall fold is similar to previously reported CDC structures, although the C-terminal domain is in a different orientation with respect to the rest of the molecule. Surprisingly, a signature stretch of CDC sequence called the undecapeptide motif, a key region involved in membrane recognition, adopts a very different structure in SLO to that of the well-characterized CDC perfringolysin O (PFO), although the sequences in this region are identical. An analysis reveals that, in PFO, there are complementary interactions between the motif and the rest of domain 4 that are lost in SLO. Molecular dynamics simulations suggest that the loss of a salt bridge in SLO and a cation-pi interaction are determining factors in the extended conformation of the motif, which in turn appears to result in a greater flexibility of the neighboring L1 loop that houses a cholesterol-sensing motif. These differences may explain the differing abilities of SLO and PFO to efficiently penetrate target cell membranes in the first step of toxin insertion into the membrane.