The Botulinum neurotoxins (BoNTs) are a family of bacterial toxins. Despite being one of the most toxic compounds known, BoNT/A and BoNT/B are extensively used therapeutically. The Botulinum neurotoxins generally achieve their high avidity and specificity for the neuron by binding two receptors. All serotypes bind gangliosides and different serotypes bind distinctive membrane protein receptors. We use structural biology and biophysics to study the binding of different botulinum neurotoxin serotypes to their protein and ganglioside receptors. We have solved the structure of a ternary complex of the binding domain of BoNT/B bound to the recognition domain of its protein receptor, Syt-II, as well as the ganglioside GD1a simultaneously, providing insight into the dual receptor binding of the BoNTs. There is a minor difference in the recognition region of Syt-II between rat/mouse and human (F54L), this has previously been believed to have minor effects. We found that this mutation drastically lowered the affinity of BoNT/B for the human Syt-II receptor. This is important for the therapeutic properties of BoNT/B. To address this problem we have developed a new BoNT/B variant with high affinity for the human receptor. In addition two recent discoveries just accepted for publication in Nature communications and JACS will be presented.


Docent Pål Stenmark, Institutionen för biokemi och biofysik, Stockholms universitet
Hemsida: http://www.su.se/english/profiles/stenm-1.182287
e-post: pal.stenmark@dbb.su.se


Biträdande professor Henrietta Nielsen, Institutionen för neurokemi