The synaptic acetylcholinesterase tetramer assembles around a polyproline II helix

Abstract

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 B4-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 AChE T tetramer.

Butyrylcholinesterase attenuates amyloid fibril formation in vitro

“…In structural modeling, both ASP40 and BSP41 peptides emerged as symmetric amphipathic helices with similar distributions of polar and nonpolar residues, compatible with findings of others (Fig. 4 B-E) (19). However, BSP41 displayed imperfect amphipathicity, locally disturbed by the protruding aromatic W8 residue in the polar side of this helix, indicating that the aromatic W8 residue in the polar side of BSP41 could potentially be responsible for the functional difference between ASP40 and BSP41.…”

“…Recent reports postulate that, for amyloid-forming proteins, a unique sidechain arrangement that, by -stacking forces, provides the energetic force supporting the formation and stabilization of the core ␤-sheet structure (22). In the majority of AChE-S and BChE molecules, the hydrophobic part of the amphipathic helix of the C terminus, is engaged in G4 homooligomers (19,23). In the AChE-S molecule, the hydrophobic PAS domain located close to the lip of the active-site gorge is free to form complexes with growing fibrils, thus supporting the A␤ assembly process (24).…”

Rescue and Stabilization of Acetylcholinesterase in Skeletal Muscle by N-terminal Peptides Derived from the Noncatalytic Subunits

“…The mechanisms responsible for the activation and stabilization of AChE subunits into catalytically active oligomers are being elucidated. For example, co-assembly of the noncatalytic ColQ and PRiMA subunits are essential for the assembly of higher order oligomeric forms such as the tetramers and the asymmetric collagen-tailed forms (14,28,29), and this occurs through the PRAD-containing N-terminal domain (7)(8)(9).…”

Acetylcholinesterase/C terminal binding protein interactions modify Ikaros functions, causing T lymphopenia

“…Importantly, the modeled ASP 67 was found to fit a trough on the surface of the modeled CtBP 2 protein (Figure 3b), that spans part of the residues involved in CtBP binding of PXDLS-containing proteins (residues R266, D290, E295 and 67 and GARP 51 vectors, encoding fusion proteins of GFP with C-terminally fused ASP 67 (the AChE-S C terminus, which served for the two-hybrid screen) and ARP 51 (which failed to interact with CtBP in a parallel screen). Note the a-helical structure of the GASP peptide (following Dvir et al 7 ) and the null structure of ARP 51 , which emerges as naturally unfolded. 38 (b) GASP 67 accumulates in nuclei whereas GARP 51 remains exclusively cytoplasmic.…”

“…The principal AChE mRNA transcript joins exon (E) 4 to E6 to give rise to acetylcholinesterase-S (AChE-S), the 'synaptic' isoform, with an amphipathic C terminus of a-helical structure. 7 Another transcript, acetylcholinesterase-R (AChE-R), expressed in embryonic and tumor cells, 8 is formed by continuous transcription through intron I4. Multiple stress stimuli involve increased ratio between AChE-R and AChE-S in brain and blood cells alike.…”