Muraro Lucia, Tosatto Silvio, Motterlini Lisa, Rossetto Ornella, Montecucco Cesare
Department of Biomedical Sciences, University of Padua, Viale G. Colombo 3, 35121 Padua, Italy.
Biochem Biophys Res Commun. 2009 Feb 27;380(1):76-80. doi: 10.1016/j.bbrc.2009.01.037. Epub 2009 Jan 20.
Botulinum neurotoxin type A (BoNT/A) is largely employed in human therapy because of its specific inhibition of peripheral cholinergic nerve terminals. BoNT/A binds to them rapidly and with high specificity via its receptor binding domain termed HC. Recent evidence indicate that BoNT/A interacts specifically with polysialogangliosides and with a luminal loop of the synaptic vesicle protein SV2 via the C-terminal half of HC. Here we show that the N-terminal half of HC binds to sphingomyelin-enriched membrane microdomains and that it has a defined interaction with phosphatidylinositol phosphates (PIP). We have identified a PIP binding site in this half of HC and we show how this interaction could predispose BoNT/A for membrane insertion, which is the step subsequent to binding, in the four-steps route leading BoNT/A inside nerve terminals.
A型肉毒杆菌神经毒素（BoNT/A）因其对周围胆碱能神经末梢的特异性抑制作用而广泛应用于人类治疗。BoNT/A通过其称为HC的受体结合结构域与它们快速且高度特异性地结合。最近的证据表明，BoNT/A通过HC的C端一半与多唾液酸神经节苷脂以及突触小泡蛋白SV2的腔内环特异性相互作用。在这里，我们表明HC的N端一半与富含鞘磷脂的膜微区结合，并且它与磷脂酰肌醇磷酸（PIP）有明确的相互作用。我们在HC的这一半中鉴定出一个PIP结合位点，并展示了这种相互作用如何使BoNT/A易于进行膜插入，这是在引导BoNT/A进入神经末梢的四步途径中结合后的后续步骤。
