The polymorphism of acetylcholinesterase: post-translational processing, quaternary associations and localization

Abstract

The molecular forms of acetylcholinesterase (AChE) correspond to various quaternary structures and modes of anchoring of the enzyme. In vertebrates, these molecules are generated from a single gene: the catalytic domain may be associated with several types of C-terminal peptides, that define distinct types of catalytic subunits (AChES, AChEH, AChET) and determine their post-translational maturation. AChES generates soluble monomers, in the venom of Elapid snakes. AChEH generates GPI-anchored dimers, in Torpedo muscles and on mammalian blood cells. AChET is the only type of catalytic subunit that exists in all vertebrate cholinesterases; it produces the major forms in adult brain and muscle. AChET generates multiple structures, ranging from monomers and dimers to collagen-tailed and hydrophobic-tailed forms, in which catalytic tetramers are associated with anchoring proteins that attach them to the basal lamina or to cell membranes. In the collagen-tailed forms, AChET subunits are associated with a specific collagen, ColQ, which is encoded by a single gene in mammals. ColQ contains a short peptidic motif, the proline-rich attachment domain (PRAD), that triggers the formation of AChET tetramers, from monomers and dimers. The critical feature of this motif is the presence of a string of prolines, and in fact synthetic polyproline shows a similar capacity to organize AChET tetramers. Although the COLQ gene produces multiple transcripts, it does not generate the hydrophobic tail, P, which anchors AChE in mammalian brain membranes. The coordinated expression of AChET subunits and anchoring proteins determines the pattern of molecular forms and therefore the localization and functionality of the enzyme.