一名韩国家族性 EOAD 患者的 PSEN1 His214Asn 突变与组氨酸-色氨酸相互作用在 TM-4 稳定性中的重要性

IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Molecular Sciences Pub Date : 2023-12-21 DOI:10.3390/ijms25010116
Eva Bagyinszky, Minju Kim, Young Ho Park, S. S. A. An, Sangyun Kim
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引用次数: 0

摘要

韩国首次在一名 41 岁记忆力衰退的男性患者身上发现了 presenilin-1(PSEN1)的致病突变 His214Asn。该患者的父亲、姑姑和祖母均有阳性家族史,但未进行基因检测。他被诊断为早发性阿尔茨海默病(EOAD)。PSEN1 His214Asn最初是在一个意大利家庭中被报道的,该家庭中的患者出现了与目前的疑似患者相似的表型。磁共振成像(MRI)扫描显示海马轻度萎缩。淀粉样蛋白正电子发射断层扫描(amyloid-PET)呈阳性,同时血液中淀粉样蛋白ß(Aβ)寡聚化倾向也呈阳性。PSEN1的His214氨基酸位置在γ-分泌酶的功能中起着重要作用,特别是在该残基上又有三个突变报道:His214Asp、His214Tyr和His214Arg。结构预测模型显示,PSEN1 蛋白中的 His214 可能与 His-Trp 阳离子-π相互作用的 Trp215 发生相互作用,而 His214 的突变将破坏这种相互作用。His214 与 Trp215 之间的 His-Trp 阳离子-π 相互作用在稳定 PSEN1 蛋白的第 4 跨膜结构域方面起着至关重要的结构作用,尤其是当芳香族残基经常出现在α螺旋或β片的脂质-胞外区域的膜界面时。His214Asn 会改变γ-分泌酶在螺旋内 His214 和 Trp215 相互作用消失后的裂解动力学,从而导致淀粉样蛋白生成量增加。因此,Aβ的增加反映在淀粉样蛋白-PET增加的Aβ寡聚化趋势和Aβ在大脑中的积累,从而导致EOAD。
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PSEN1 His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine–Tryptophan Interactions in TM-4 Stability
A pathogenic mutation in presenilin-1 (PSEN1), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient was associated with a positive family history from his father, paternal aunt, and paternal grandmother without genetic testing. He was diagnosed with early onset Alzheimer’s disease (EOAD). PSEN1 His214Asn was initially reported in an Italian family, where the patient developed phenotypes similar to the current proband patient. Magnetic resonance imaging (MRI) scans revealed a mild hippocampal atrophy. The amyloid positron emission tomography (amyloid-PET) was positive, along with the positive test results of the increased amyloid ß (Aβ) oligomerization tendency with blood. The PSEN1 His214 amino acid position plays a significant role in the gamma–secretase function, especially from three additional reported mutations in this residue: His214Asp, His214Tyr, and His214Arg. The structure prediction model revealed that PSEN1 protein His214 may interact with Trp215 of His-Trp cation-π interaction, and the mutations of His214 would destroy this interaction. The His-Trp cation-π interaction between His214 and Trp215 would play a crucial structural role in stabilizing the 4th transmembrane domain of PSEN1 protein, especially when aromatic residues were often reported in the membrane interface of the lipid–extracellular region of alpha helices or beta sheets. The His214Asn would alter the cleavage dynamics of gamma–secretase from the disappeared interactions between His214 and Trp215 inside of the helix, resulting in elevated amyloid production. Hence, the increased Aβ was reflected in the increased Aβ oligomerization tendency and the accumulations of Aβ in the brain from amyloid-PET, leading to EOAD.
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来源期刊
International Journal of Molecular Sciences
International Journal of Molecular Sciences Chemistry-Organic Chemistry
CiteScore
8.10
自引率
10.70%
发文量
13472
审稿时长
17.49 days
期刊介绍: The International Journal of Molecular Sciences (ISSN 1422-0067) provides an advanced forum for chemistry, molecular physics (chemical physics and physical chemistry) and molecular biology. It publishes research articles, reviews, communications and short notes. Our aim is to encourage scientists to publish their theoretical and experimental results in as much detail as possible. Therefore, there is no restriction on the length of the papers or the number of electronics supplementary files. For articles with computational results, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material (including animated pictures, videos, interactive Excel sheets, software executables and others).
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