Specific membrane binding of neurotoxin II can facilitate its delivery to acetylcholine receptor.
The action of three-finger snake alpha-neurotoxins at their targets, nicotinic acetylcholine receptors (nAChR), is widely studied because of its biological and pharmacological relevance. Most such studies deal only with ligands and receptor models; however, for many ligand/receptor systems the membrane environment may affect ligand binding. In this work we focused on binding of short-chain alpha-neurotoxin II (NTII) from Naja oxiana to the native-like lipid bilayer, and the possible role played by the membrane in delivering the toxin to nAChR. Experimental (NMR and mutagenesis) and molecular modeling (molecular-dynamics simulation) studies revealed a specific interaction of the toxin molecule with the phosphatidylserine headgroup of lipids, resulting in the proper topology of NTII on lipid bilayers favoring the attack of nAChR. Analysis of short-chain alpha-neurotoxins showed that most of them possess a high positive charge and sequence homology in the lipid-binding motif of NTII, implying that interaction with the membrane surrounding nAChR may be common for the toxin family.
Lesovoy
Dmitry M
DM
Division of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia.
Bocharov
Eduard V
EV
Lyukmanova
Ekaterina N
EN
Kosinsky
Yurij A
YA
Shulepko
Mikhail A
MA
Dolgikh
Dmitry A
DA
Kirpichnikov
Mikhail P
MP
Efremov
Roman G
RG
Arseniev
Alexander S
AS
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D032701:Biomimetics; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D017815:Elapidae; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D009498:Neurotoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D011950:Receptors, Cholinergic / Q000378:metabolism*; D013379:Substrate Specificity; D013499:Surface Properties; D014101:Torpedo
D008051:Lipid Bilayers; D008081:Liposomes; D009498:Neurotoxins; D011950:Receptors, Cholinergic