The N-terminal half of the receptor domain of botulinum neurotoxin A binds to microdomains of the plasma membrane

• Published in: Biochemical and biophysical research communications Vol. 380; no. 1; pp. 76 - 80
• Main Authors: Muraro, Lucia, Tosatto, Silvio, Motterlini, Lisa, Rossetto, Ornella, Montecucco, Cesare
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27-02-2009
• Subjects: Botulinum neurotoxin; Botulinum Toxins, Type A - chemistry; Botulinum Toxins, Type A - genetics; Botulinum Toxins, Type A - metabolism; Botulism; HeLa Cells; Humans; Membrane binding; Membrane Microdomains - chemistry; Membrane Microdomains - metabolism; Models, Molecular; Phosphatidylinositol Phosphates - chemistry; Phosphatidylinositol Phosphates - metabolism; PIP; Protein Structure, Tertiary - genetics; Sphingomyelin; PS; HN; H; Botulinum neurotoxin; EGFP; L; SNARE; S; PIP, PIP, PIP; Membrane binding; PI(3,4,5)P; SM; mCherry; CL; DAG; BoNT; PI(3,4)P, PI(3,5)P, PI(4,5)P; PA; Hc-C; TG; PC; Botulism; PE; PIP; PG; Sphingomyelin; PI; HC; Hc-N
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2009.01.037

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.