The N-terminal half of the receptor domain of botulinum neurotoxin A binds to microdomains of the plasma membrane.
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.
Muraro
Lucia
L
Department of Biomedical Sciences, University of Padua, Viale G. Colombo 3, 35121 Padua, Italy.
Tosatto
Silvio
S
Motterlini
Lisa
L
Rossetto
Ornella
O
Montecucco
Cesare
C
D019274:Botulinum Toxins, Type A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics
D018129:Phosphatidylinositol Phosphates; D019274:Botulinum Toxins, Type A