Botulinum neurotoxin light chain refolds at endosomal pH for its translocation.
Botulinum neurotoxins (BoNTs), the most poisonous member of class A biothreat agent, cause neuroparalysis by blocking neurotransmitter release at the neuromuscular junctions. In its mechanism of action, the catalytic domain (light chain (LC) of BoNT) is transported to the cytosol by the heavy chain (HC) in order to reach its proteolytic substrates. The BoNT HC forms a membrane channel under acidic conditions encountered in endosomes to serve as a passageway for LC to enter into cytosol. We demonstrate here that BoNT/A LC undergoes unique structural changes under the low pH conditions, and adopts a molten globule state, exposing substantial number of hydrophobic groups. The flexibility of the molten globular structure combined with retention of the secondary structure and exposure of specific residues of LC for interaction with the HC, allows its translocation through the narrow endosomal membrane channel.
Cai
Shuowei
S
Botulinum Research Center, University of Massachusetts Dartmouth, North Dartmouth, MA, 02747, USA. scai@umassd.edu
Kukreja
Roshan
R
Shoesmith
Sue
S
Chang
Tzuu-Wang
TW
Singh
Bal Ram
BR
D000817:Anilino Naphthalenesulfonates; D001905:Botulinum Toxins / Q000737:chemistry*; D002942:Circular Dichroism; D011992:Endosomes / Q000737:chemistry; D005453:Fluorescence; D005456:Fluorescent Dyes; D006863:Hydrogen-Ion Concentration; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D014364:Tryptophan / Q000737:chemistry
D000817:Anilino Naphthalenesulfonates; D005456:Fluorescent Dyes; C027132:1-anilino-8-naphthalenesulfonate; D014364:Tryptophan; D001905:Botulinum Toxins