Structure-based sequence alignment for the beta-trefoil subdomain of the clostridial neurotoxin family provides residue level information about the putative ganglioside binding site.
Clostridial neurotoxins embrace a family of extremely potent toxins comprised of tetanus toxin (TeNT) and seven different serotypes of botulinum toxin (BoNT/A-G). The beta-trefoil subdomain of the C-terminal part of the heavy chain (H(C)), responsible for ganglioside binding, is the most divergent region in clostridial neurotoxins with sequence identity as low as 15%. We re-examined the alignment between family sequences within this subdomain, since in this region all alignments published to date show obvious inconsistencies with the beta-trefoil fold. The final alignment was obtained by considering the general constraints imposed by this fold, and homology modeling studies based on the TeNT structure. Recently solved structures of BoNT/A confirm the validity of this structure-based approach. Taking into account biochemical data and crystal structures of TeNT and BoNT/A, we also re-examined the location of the putative ganglioside binding site and, using the new alignment, characterized this site in other BoNT serotypes.
Ginalski
K
K
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, CA 94551, USA. kginal@icm.edu.pl
Venclovas
C
C
Lesyng
B
B
Fidelis
K
K
D000595:Amino Acid Sequence; D001905:Botulinum Toxins / Q000737:chemistry*; D003013:Clostridium; D017124:Conserved Sequence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013744:Tetanus Toxin / Q000737:chemistry*
D013744:Tetanus Toxin; D001905:Botulinum Toxins