RT Journal Article
SR Electronic
T1 The physiological butyrylcholinesterase tetramer is a dimer of dimers stabilized by a superhelical assembly
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 431288
DO 10.1101/431288
A1 Miguel Ricardo Leung
A1 Laura S. van Bezouwen
A1 Lawrence M. Schopfer
A1 Joel L. Sussman
A1 Israel Silman
A1 Oksana Lockridge
A1 Tzviya Zeev-Ben-Mordehai
YR 2018
UL http://biorxiv.org/content/early/2018/09/30/431288.abstract
AB The quaternary structures of the cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are essential for their localisation and function. Of practical importance, BChE is a promising therapeutic candidate for intoxication by organophosphate nerve agents and insecticides, and for detoxification of addictive substances. Efficacy of the recombinant enzyme hinges on its having a long circulatory half-life; this, in turn, depends strongly on its ability to tetramerize. Here, we used cryo-electron microscopy (cryo-EM) to determine the structure of the highly glycosylated native BChE tetramer purified from human plasma at 5.7 Å. Our structure reveals that the BChE tetramer is organised as a staggered dimer of dimers. Tetramerization is mediated by assembly of the C-terminal tryptophan amphiphilic tetramerization (WAT) helices from each subunit as a superhelical assembly around a central anti-parallel polyproline II helix (PRAD). The catalytic domains within a dimer are asymmetrically linked to the WAT/PRAD. In the resulting arrangement, the tetramerization domain is largely shielded by the catalytic domains, which may contribute to the stability of the HuBChE tetramer. Our cryo-EM structure reveals the basis for assembly of the physiological tetramers, and has implications for the therapeutic applications of HuBChE. This mode of tetramerization is seen only in the cholinesterases, and may provide a promising template for designing other proteins with improved circulatory residence times.