Structural Switch from Hairpin to Duplex/AntiparallelG-Quadruplex at Single-Nucleotide Polymorphism (SNP) Site ofHuman Apolipoprotein E (APOE) Gene Coding Region

摘要

A gradual dementia, which leads to the loss of memory and intellectual abilities, is the main characteristics of Alzheimer’s disease. Amyloid-β (Aβ) plaques are the main components that accumulate and form clumps in the brains of people suffering from Alzheimer’s disease. Apolipoprotein E (APOE), an amyloid-binding protein is considered as one of the main genetic risk factor of the late-onset Alzheimer’s disease. Different isoforms of APOE gene named APOE2, APOE3, and APOE4 are known to exist, which differ from each other at certain positions involving single-nucleotide polymorphisms (SNPs). Out of these isoforms, APOE4 increases the risk of developing late-onset Alzheimer’s disease, whereas APOE3 is the most common among the general population. APOE4 differs from the common APOE3 by only one nucleotide at position +2985 (T to C), which results in immense alteration in the structure and function of the APOE gene. A combination of gel electrophoresis (polyacrylamide gel electrophoresis, PAGE), circular dichroism (CD), CD melting, thermal difference spectra and UV-thermal denaturation(TM) techniques was used to investigatethe structural polymorphism associated with T → C single-nucleotidepolymorphism (SNP) at the GC-rich sequence (d-TGGAGGACGTGTGCGGCCGCCT; APOE22T). Herein, we report that APOE22TDNA sequence switches between hairpin to antiparallel quadruplex fromlow to high oligomer concentration. On the contrary, its C-counterpart(APOE22C) forms hairpin as well as intermolecular antiparallel duplexstructure. This structural change may possibly contribute to the proteinrecognition pattern, which, in turn, might control the APOE gene expression.