Measuring the strength of interaction between the ebola fusion peptide and lipid rafts: implications for membrane fusion and virus infection
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Abstract
9 p. : il., tab.The Ebola fusion peptide (EBO16) is a hydrophobic domain that belongs to the GP2 membrane fusion protein of the Ebola
virus. It adopts a helical structure in the presence of mimetic membranes that is stabilized by the presence of an aromaticaromatic
interaction established by Trp8 and Phe12. In spite of its infectious cycle becoming better understood recently,
several steps still remain unclear, a lacuna that makes it difficult to develop strategies to block infection. In order to gain
insight into the mechanism of membrane fusion, we probed the structure, function and energetics of EBO16 and its mutant
W8A, in the absence or presence of different lipid membranes, including isolated domain-resistant membranes (DRM), a
good experimental model for lipid rafts. The depletion of cholesterol from living mammalian cells reduced the ability of
EBO16 to induce lipid mixing. On the other hand, EBO16 was structurally sensitive to interaction with lipid rafts (DRMs), but
the same was not observed for W8A mutant. In agreement with these data, W8A showed a poor ability to promote
membrane aggregation in comparison to EBO16. Single molecule AFM experiments showed a high affinity force pattern for
the interaction of EBO16 and DRM, which seems to be a complex energetic event as observed by the calorimetric profile. Our
study is the first to show a strong correlation between the initial step of Ebola virus infection and cholesterol, thus providing
a rationale for Ebola virus proteins being co-localized with lipid-raft domains. In all, the results show how small fusion
peptide sequences have evolved to adopt highly specific and strong interactions with membrane domains. Such features
suggest these processes are excellent targets for therapeutic and vaccine approaches to viral diseases