Acetylcholinesterase: C-terminal domains, molecular forms and functional localization

Massoulié, Jean; Anselmet, Alain; Bon, Suzanne; Krejci, Éric; Legay, Claire; Morel, Nathalie; Simon, Stéphanie

doi:10.1016/s0928-4257(98)80007-7

Cited by 67 publications

(54 citation statements)

References 53 publications

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“…Moreover, the alternative splicing mechanism that controls the nature of the membrane attachment of AChE also influences its degree of its oligomerization. Homomeric dimers and tetramers have been identified, as have heteromeric associations between catalytic and structural subunits (13,29,30).…”

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confidence: 99%

A Mutation Linked with Autism Reveals a Common Mechanism of Endoplasmic Reticulum Retention for the α,β-Hydrolase Fold Protein Family

Jaco

Comoletti

Kovarik

et al. 2006

Journal of Biological Chemistry

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A mutation linked to autistic spectrum disorders encodes an Arg to Cys replacement in the C-terminal portion of the extracellular domain of neuroligin-3. The solvent-exposed Cys causes virtually complete retention of the protein in the endoplasmic reticulum when the protein is expressed in transfected cells. An identical Cys substitution was reported for butyrylcholinesterase through genotyping patients with post-succinylcholine apnea. Neuroligin, butyrylcholinesterase, and acetylcholinesterase are members of the ␣,␤-hydrolase fold family of proteins sharing sequence similarity and common tertiary structures. Although these proteins have distinct oligomeric assemblies and cellular dispositions, homologous Arg residues in neuroligin-3 (Arg-451), in butyrylcholinesterase (Arg-386), and in acetylcholinesterase (Arg-395) are conserved in all studied mammalian species. To examine whether an homologous Arg to Cys mutation affects related proteins similarly despite their differing capacities to oligomerize, we inserted homologous mutations in the acetylcholinesterase and butyrylcholinesterase cDNAs. Using confocal fluorescence microscopy and analysis of oligosaccharide processing, we find that the homologous Arg to Cys mutation also results in endoplasmic reticulum retention of the two cholinesterases. Small quantities of mutated acetylcholinesterase exported from the cell retain activity but show a greater K m , a much smaller k cat , and altered substrate inhibition. The nascent proteins associate with chaperones during processing, but the mutation presumably restricts processing through the endoplasmic reticulum and Golgi apparatus, because of local protein misfolding and inability to oligomerize. The mutation may alter the capacity of these proteins to dissociate from their chaperone prior to oligomerization and processing for export.

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confidence: 99%

A Mutation Linked with Autism Reveals a Common Mechanism of Endoplasmic Reticulum Retention for the α,β-Hydrolase Fold Protein Family

Jaco

Comoletti

Kovarik

et al. 2006

Journal of Biological Chemistry

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“…Soluble monomers (G1), dimers (G2), and tetramers (G4) are composed of T subunits. In addition these tetramers may be associated with structural subunits, a collagenic tail in neuromuscular junctions, or a membrane protein in brain (9). In some cases, the genomic sequence following the last common exon is retained into the mRNA.…”

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confidence: 99%

“…In some cases, the genomic sequence following the last common exon is retained into the mRNA. Physiological significance of this readthrough transcript is not known (9).…”

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confidence: 99%

Zebrafish Acetylcholinesterase Is Encoded by a Single Gene Localized on Linkage Group 7

Bertrand¹,

Chatonnet²,

Takke³

et al. 2001

Journal of Biological Chemistry

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We cloned and sequenced the acetylcholinesterase gene and cDNA of zebrafish, Danio rerio. We found a single gene (ache) located on linkage group LG7. The relative organization of ache, eng2, and shh genes is conserved between zebrafish and mammals and defines a synteny. Restriction fragment length polymorphism analysis was allowed to identify several allelic variations. We also identified two transposable elements in non-coding regions of the gene. Compared with other vertebrate acetylcholinesterase genes, ache gene contains no alternative splicing at 5 or 3 ends where only a T exon is present. The translated sequence is 60 -80% identical to acetylcholinesterases of the vertebrates and exhibits an extra loop specific to teleosts. Analysis of molecular forms showed a transition, at the time of hatching, from the globular G4 form to asymmetric A12 form that becomes prominent in adults. In situ hybridization and enzymatic activity detection on whole embryos confirmed early expression of the acetylcholinesterase gene in nervous and muscular tissues. We found no butyrylcholinesterase gene or activity in Danio. These findings make zebrafish a promising model to study function of acetylcholinesterase during development and regulation of molecular forms assembly in vivo.

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“…The "synaptic" isoform, AChE-S, is C-terminated by a unique 40-residue sequence, the cysteine residue of which enables dimerization. Up to to three tetramers can interact with the collagen triple helix-like ColQ structural subunit characteristic of the neuromuscular junction (reviewed by Massoulie et al 1998). "Erythrocytic" AChE-E is C-terminated by its unique 14-residue peptide which enables linkage to the erythrocyte membrane through glycophosphatidoinositide groups (Futerman, et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

“…The catalytically active core domain of all AChE isoforms is derived from the common exons, resulting in only very small differences between the variants in their affinities for both substrates and inhibitors. In contrast, the alternative C-terminal peptides impose diverse biophysical properties upon the various isoforms that determine hydrophobicity, modes of oligomeric assembly, interactions with non-catalytic subunits and subcellular localization (Reviewed by Massoulie et al, 1998). Figure 2.…”

mentioning

confidence: 99%

Genetic and Epigenetic Mechanisms Underlying Acute and Delayed Neurodegenerative Consequences of Stress and Anticholinesterase Exposure

Soreq¹

2003

PsycEXTRA Dataset

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075REPORT Public reportinq burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing date sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect cif this collection of 'mormaton, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, andtotheOfficeof Vanaqement and Budget, Paperwork Reduction Project (0704-0188) soreq@shum.huji.ac.il SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U SUPPLEMENTARY NOTESReport contains color graphics. 12a. DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release; Distribution unlimited 12b. DISTRIBUTION CODE ABSTRACT (Maximum 200 Words)To characterize neuropathological consequences of excess acetylcholinesterase (AChE), we employed transgenic mice developed under previous US Army support. These mice demonstrated association between such excess and adverse responses (in brain and intestine) to pyridostigmine and diisopropylfluorophosphonate. The stress-associated "readthrough" AChE-R variant was seen also in progenitor blood cells, suggesting its use as a surrogate marker for anti-AChE responses. Moreover, AChE-R accumulates in the brain following head injury, its pre-injury excess exacerbates damage, and its antisense suppression improves survival and recovery. Using a 2-hybrid yeast screen we discovered a previously unknown interaction of AChE-R with RACK1, a protein kinase cargo protein involved in signaling processes. Animals carrying a tetracycline-inducible anti-AChE antisense sequence are being characterized for further studies of these interactions. At the extended promoter of the ACHE gene, we found a 4 bp deletion that over-induces transcription and hypersensitivity to pyridostigmine through impairment of HNF3B interaction, and discovered a novel mutation that disrupts the glucocorticoid binding site. Finally, we found AChE-R-specific inhibitor interactions in mouse brain that reflect the specific increase in the AChE-R variant after psychological stress. ( The AChE-R variant thus emerges as the key scavenger and acetylcholine-hydrolyzing agent in several mammalian tissues under various stress insults. Table of contents 3 Introduction 4 Body task 1: characterize the sensory, cognitive and neuromotor consequences of a 5 transgenic excess in AChE variants. task 2: employ transgenic mouse models with up to 300-fold differences in 10 peripheral AChE levels for demonstration of direct correlation between AChE dosage and protection from stress and chemical warfare agents and to test their responses to pyridostigmine administration. task 3: develop RT-PCR tests in peripheral blood cells of model animals, and 12 additional surrogate markers, for follow-up of responses and protection task 5: emplo...

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Acetylcholinesterase: C-terminal domains, molecular forms and functional localization

Cited by 67 publications

References 53 publications

A Mutation Linked with Autism Reveals a Common Mechanism of Endoplasmic Reticulum Retention for the α,β-Hydrolase Fold Protein Family

A Mutation Linked with Autism Reveals a Common Mechanism of Endoplasmic Reticulum Retention for the α,β-Hydrolase Fold Protein Family

Zebrafish Acetylcholinesterase Is Encoded by a Single Gene Localized on Linkage Group 7

Genetic and Epigenetic Mechanisms Underlying Acute and Delayed Neurodegenerative Consequences of Stress and Anticholinesterase Exposure

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