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| Subject Categories: Structural Biology | Neuroscience |
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| The EMBO Journal
(2004) 23, 4394–4405, doi:10.1038/sj.emboj.7600425 Published online 4 November 2004 |
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| The synaptic acetylcholinesterase tetramer assembles around a polyproline II helix |
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| Hay Dvir1, 2, 5, Michal Harel1, 5, Suzanne Bon3, Wang-Qing Liu4, Michel Vidal4, Christiane Garbay4, Joel L Sussman1, Jean Massoulié3 and Israel Silman2 |
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1 Dapartment of Structural Biology, Weizmann Institute of Science, Rehovot, Israel 2 Dapartment of Neurobiology, Weizmann Institute of Science, Rehovot, Israel 3 École Normale Supérieure, Paris, France 4 Laboratoire de Pharmacochimie Moléculaire et Structurale, Faculté de Pharmacie, Paris, France To whom correspondence should be addressed Joel L Sussman, Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: +972 8 934 4531; Fax: +972 8 934 4159; E-mail: Joel.Sussman@weizmann.ac.il Israel Silman, Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: +972 8 934 3649; Fax: +972 8 934 6017; E-mail: Israel.Silman@weizmann.ac.il 5 These authors contributed equally to this work Received 10 May 2004; Accepted 31 August 2004; Published online 4 November 2004. |
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| Abstract |
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Functional localization of acetylcholinesterase (AChE) in vertebrate muscle and brain depends on interaction of the tryptophan amphiphilic tetramerization (WAT) sequence, at the C-terminus of its major splice variant (T), with a proline-rich attachment domain (PRAD), of the anchoring proteins, collagenous (ColQ) and proline-rich membrane anchor. The crystal structure of the WAT/PRAD complex reveals a novel supercoil structure in which four parallel WAT chains form a left-handed superhelix around an antiparallel left-handed PRAD helix resembling polyproline II. The WAT coiled coils possess a WWW motif making repetitive hydrophobic stacking and hydrogen-bond interactions with the PRAD. The WAT chains are related by an  4-fold screw axis around the PRAD. Each WAT makes similar but unique interactions, consistent with an asymmetric pattern of disulfide linkages between the AChE tetramer subunits and ColQ. The P59Q mutation in ColQ, which causes congenital endplate AChE deficiency, and is located within the PRAD, disrupts crucial WAT–WAT and WAT–PRAD interactions. A model is proposed for the synaptic AChET tetramer. |
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| Keywords: acetylcholinesterase, polyproline II, tetramerization domain, WWW motif, X-ray structure |
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