Botulinum neurotoxin type A heavy chain receptor-binding domain (BoNT/A-Hc)

The Botulinum neurotoxin type A heavy chain receptor-binding domain (BoNT/A-Hc) is the 50 kDa C-terminal portion of the heavy chain of the neurotoxin produced by Clostridium botulinum [1]. It is responsible for the initial and highly specific step of the toxin's mechanism: binding to the presynaptic membrane of motor neurons [2]. This binding is achieved through a dual-receptor model, where the domain interacts with both complex polysialogangliosides and the synaptic vesicle protein 2 (SV2), specifically isoforms A, B, and C [3]. By facilitating the attachment and subsequent receptor-mediated endocytosis of the toxin, the Hc domain ensures the delivery of the catalytic light chain into the neuronal cytosol [4]. In clinical practice, this domain is the functional component of therapeutic agents like OnabotulinumtoxinA, used to treat neuromuscular disorders and for cosmetic purposes [2]. Conversely, it serves as a primary target for the development of neutralizing antibodies and vaccines intended to prevent or treat botulism [5]. Understanding the structural biology of this domain is essential for engineering next-generation toxins with altered specificity or duration of action [4].

Other names

BoNT/A-HcHc domain of Botulinum neurotoxin AC-terminal fragment of BoNT/A heavy chainBoNT/A-Hcc

The Hc domain mediates high-affinity binding to the synaptic vesicle protein SV2 and gangliosides on the presynaptic nerve terminal, facilitating the entry of the toxin's light chain into the cytosol to cleave SNAP-25 [3, 4].