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High-throughput Measurement of Plasma Membrane Resealing Efficiency in Mammalian Cells
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Structural Basis for Receptor Recognition by the Human CD59-Responsive Cholesterol-Dependent Cytolysins
Sara L Lawrence1, Michael A Gorman1, Susanne C Feil1
1ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
Structure (London, England : 1993)
|August 9, 2016
Summary
Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins. Structural studies reveal how CD59 binding directs CDCs to cell membranes, with proline acting as a selectivity switch.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins targeting eukaryotic cell membranes.
- While cholesterol is a primary receptor, some CDCs bind human CD59 first.
Purpose of the Study:
- To determine the crystal structures of vaginolysin and intermedilysin complexed with CD59.
- To elucidate the binding mechanism and selectivity of CD59-dependent CDCs.
Main Methods:
- X-ray crystallography
- Small-angle X-ray scattering (SAXS)
- Molecular dynamics simulations
- Binding studies
Main Results:
- Crystal structures reveal distinct binding sites of CD59 on vaginolysin and intermedilysin.
- The CDC undecapeptide motif shows different conformations, with proline acting as a selectivity switch for CD59 binding.
- A model for prepore assembly on cell surfaces is proposed.
Conclusions:
- CD59 binding is mediated by specific, overlapping sites on different CDCs.
- Proline in the CDC motif confers selectivity for protein receptors over cholesterol.
- Structural insights provide a foundation for understanding CDC-host interactions and pore formation.
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