Macrocyclic Peptides Derived from Familial Alzheimer's Disease Mutants Show Charge-Dependent Oligomeric Assembly and Toxicity.
Macrocyclic Peptides Derived from Familial Alzheimer's Disease Mutants Show Charge-Dependent Oligomeric Assembly and Toxicity.
复制标题
DOI：
10.1021/acschemneuro.1c00833
复制
发表时间：
2022-03-16
影响因子：
5
通讯作者：
Nowick JS
中科院分区：
文献类型：
--
作者：
Howitz WJ;Guaglianone G;McKnelly KJ;Haduong K;Ashby SN;Laayouni M;Nowick JS
本工作探讨了电荷在Aβ和E22 Q和E22 K家族突变体衍生的一系列肽的寡聚体组装、毒性和膜不稳定性中的作用。在突变Aβ肽中，酸性残基（E）被中性或碱性残基（Q或K）取代，从而改变了肽的净电荷。在外围位置的乙酰化允许调节肽的电荷，并允许调查电荷在其低聚物组装、细胞毒性和膜破坏中的作用。具有相同净电荷的肽通常表现相似，即使22位的氨基酸残基不同。随着肽的净电荷减少，组装、细胞毒性和膜去稳定化的程度也减少，这使用SDS-PAGE、SH-SY 5 Y细胞的LDH释放测定和使用脂质体的染料渗漏测定来确定。这些发现表明，氨基酸侧链的电荷，而不是其大小或疏水性，解释了Aβ E22家族突变体的寡聚体组装和毒性的差异。
This work probes the role of charge in the oligomeric assembly, toxicity, and membrane destabilization of a series of peptides derived from Aβ and the E22Q and E22K familial mutants. In the mutant Aβ peptides, an acidic residue (E) is replaced with either a neutral or basic residue (Q or K), thus altering the net charge of the peptide. Acetylation at peripheral positions permits modulation of charge of the peptides and allows investigation of the role of charge in their oligomeric assembly, cytotoxicity, and membrane disruption. Peptides with the same net charge generally behave similarly even if the amino acid residue at position 22 differs. As the net charge of the peptide decreases, so does the extent of assembly, cytotoxicity, and membrane destabilization, which were determined using SDS-PAGE, LDH-release assays with SH-SY5Y cells, and dye leakage assays using liposomes. These findings suggest that the charge of the amino acid side chain, rather than its size or hydrophobicity, accounts for the differences in the oligomeric assembly and toxicity of the E22 familial mutants of Aβ.
登录
查看更多内容
影响因子：
2.9
作者：
McKnelly, Kate J.;Kreutzer, Adam G.;Howitz, William J.;Haduong, Katelyn;Yoo, Stan;Hart, Candace;Nowick, James S.
通讯作者：
Nowick, James S.
影响因子：
3.8
作者：
Camino, Jose D.;Gracia, Pablo;Cremades, Nunilo
通讯作者：
Cremades, Nunilo
影响因子：
4.8
作者：
Hughes, E;Burke, RM;Doig, AJ
通讯作者：
Doig, AJ
影响因子：
6.1
作者：
Betts, Vicki;Leissring, Malcolm A.;Walsh, Dominic M.
通讯作者：
Walsh, Dominic M.
影响因子：
5.4
作者：
Johansson, Ann-Sofi;Berglind-Dehlin, Fredrik;Lannfelt, Lars
通讯作者：
Lannfelt, Lars