タンパク質と糖の相互作用を研究した結果、驚くべき結果が得られる Study of protein-sugar interaction yields surprising results
2023-05-24 レンセラー工科大学 (RPI)
◆ApoEはコレステロールの輸送に関与するタンパク質であり、HSは細胞間の通信に重要な役割を果たす糖分子です。彼らは、ApoE4の変異体がアルツハイマー病のリスクを増加させる理由を探るために、ApoE4だけでなく他のApoE遺伝子型も調査しました。その結果、HSの3-O-スルフォ修飾がApoE/HSの相互作用に重要であり、アルツハイマー病のリスクと関連していることが明らかになりました。この研究は、病気の進行を遅らせる可能性のある新しい薬物標的を示唆しています。
<関連情報>
- https://news.rpi.edu/content/2023/05/24/rensselaer-researchers-find-new-potential-drug-target-alzheimer%E2%80%99s-disease
- https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202212636
アポリポタンパク質Eがアルツハイマー病に関連するヘパラン硫酸の3-O硫酸化を認識することが判明 Apolipoprotein E Recognizes Alzheimer’s Disease Associated 3-O Sulfation of Heparan Sulfate
Dylan Mah, Yanan Zhu, Guowei Su, Jing Zhao, Ashely Canning, James Gibson, Xuehong Song, Eduardo Stancanelli, Yongmei Xu, Fuming Zhang, Robert J. Linhardt, Jian Liu, Lianchun Wang, Chunyu Wang
Angewandte Chemie International Edition Published: 04 April 2023
DOI:https://doi.org/10.1002/anie.202212636
Graphical Abstract
The interaction of Apolipoprotein E (ApoE) with cell surface Heparan Sulfate (HS) is enhanced by a rare, Alzheimer’s Disease linked 3-O-Sulfo group. This binding motif is shared with tau protein, suggesting a mechanism for ApoE/tau interactions in the association of certain ApoE isoforms with AD.
Abstract
Apolipoprotein E (ApoE)’s ϵ4 alle is the most important genetic risk factor for late onset Alzheimer’s Disease (AD). Cell-surface heparan sulfate (HS) is a cofactor for ApoE/LRP1 interaction and the prion-like spread of tau pathology between cells. 3-O-sulfo (3-O-S) modification of HS has been linked to AD through its interaction with tau, and enhanced levels of 3-O-sulfated HS and 3-O-sulfotransferases in the AD brain. In this study, we characterized ApoE/HS interactions in wildtype ApoE3, AD-linked ApoE4, and AD-protective ApoE2 and ApoE3-Christchurch. Glycan microarray and SPR assays revealed that all ApoE isoforms recognized 3-O-S. NMR titration localized ApoE/3-O-S binding to the vicinity of the canonical HS binding motif. In cells, the knockout of HS3ST1-a major 3-O sulfotransferase-reduced cell surface binding and uptake of ApoE. 3-O-S is thus recognized by both tau and ApoE, suggesting that the interplay between 3-O-sulfated HS, tau and ApoE isoforms may modulate AD risk.
