The Butyrylcholinesterase K Variant Confers Structurally Derived Risks for Alzheimer Pathology*♦
| Autor: | Hermona Soreq, Oded Livnah, Deborah E. Shalev, Estelle R. Bennett, Erez Podoly, Einor Ben Assayag, Shani Shenhar-Tsarfaty, Harvey Wilgus |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
Molecular Sequence Data Peptide Biology Biochemistry Neuroprotection Polymorphism Single Nucleotide Protein Structure Secondary Cell Line Alzheimer Disease Risk Factors medicine Humans Genomics Proteomics and Bioinformatics Amino Acid Sequence Protein Structure Quaternary Molecular Biology Peptide sequence Butyrylcholinesterase Aged DNA Primers chemistry.chemical_classification Neurons Amyloid beta-Peptides Base Sequence C-terminus Neurotoxicity Genetic Variation Cell Biology Middle Aged medicine.disease Recombinant Proteins Neuroprotective Agents chemistry Amino Acid Substitution Cell culture Female Acetylcholine medicine.drug |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | The K variant of butyrylcholinesterase (BChE-K, 20% incidence) is a long debated risk factor for Alzheimer disease (AD). The A539T substitution in BChE-K is located at the C terminus, which is essential both for BChE tetramerization and for its capacity to attenuate beta-amyloid (Abeta) fibril formation. Here, we report that BChE-K is inherently unstable as compared with the "usual" BChE (BChE-U), resulting in reduced hydrolytic activity and predicting prolonged acetylcholine maintenance and protection from AD. A synthetic peptide derived from the C terminus of BChE-K (BSP-K), which displayed impaired intermolecular interactions, was less potent in suppressing Abeta oligomerization than its BSP-U counterpart. Correspondingly, highly purified recombinant human rBChE-U monomers suppressed beta-amyloid fibril formation less effectively than dimers, which also protected cultured neuroblastoma cells from Abeta neurotoxicity. Dual activity structurally derived changes due to the A539T substitution can thus account for both neuroprotective characteristics caused by sustained acetylcholine levels and elevated AD risk due to inefficient interference with amyloidogenic processes. |
| Databáze: | OpenAIRE |
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