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The synaptic acetylcholinesterase tetramer assembles around a polyproline II helix
Hay Dvir1, Michal Harel, Suzanne Bon
1Dapartment of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.
The EMBO Journal
|November 5, 2004
Summary
The study reveals the crystal structure of acetylcholinesterase (AChE) interacting with anchoring proteins, detailing a novel supercoil complex. This structure explains how mutations cause congenital endplate AChE deficiency.
Area of Science:
- Biochemistry
- Structural Biology
- Neuroscience
Background:
- Acetylcholinesterase (AChE) functional localization in vertebrate muscle and brain relies on interactions between its C-terminal tryptophan amphiphilic tetramerization (WAT) sequence and the proline-rich attachment domain (PRAD) of anchoring proteins like collagenous (ColQ).
- Understanding this interaction is crucial for comprehending synaptic AChE assembly and function.
Purpose of the Study:
- To determine the crystal structure of the WAT/PRAD complex.
- To elucidate the molecular mechanisms underlying AChE anchoring and the impact of mutations on this process.
Main Methods:
- X-ray crystallography was employed to determine the structure of the WAT/PRAD complex.
- Structural analysis focused on identifying key interaction motifs and the effects of mutations.
Main Results:
- A novel left-handed superhelix structure was revealed, with four parallel WAT chains coiling around an antiparallel PRAD helix.
- The WAT coiled coils feature a WWW motif facilitating hydrophobic stacking and hydrogen bonds with PRAD, forming a stable complex.
- The P59Q mutation in ColQ disrupts critical WAT-WAT and WAT-PRAD interactions, explaining congenital endplate AChE deficiency.
Conclusions:
- The crystal structure provides a detailed molecular model for the synaptic AChE(T) tetramer assembly.
- This finding clarifies the structural basis of AChE anchoring and the pathogenesis of related neuromuscular disorders.