Roychaudhuri Robin, Huynh Tien-Phat V, Whitaker Taylor R, Hodara Elisabeth, Condron Margaret M, Teplow David B
Department of Neurology, David Geffen School of Medicine at UCLA , Los Angeles, California 90095, United States.
Molecular Biology Institute and Brain Research Institute, University of California , Los Angeles, California 90095, United States.
Biochemistry. 2017 Dec 5;56(48):6321-6324. doi: 10.1021/acs.biochem.7b00772. Epub 2017 Nov 16.
Amyloid β-protein (Aβ) assembly is a seminal process in Alzheimer's disease. Elucidating the mechanistic features of this process is thought to be vital for the design and targeting of therapeutic agents. Computational studies of the most pathologic form of Aβ, the 42-residue Aβ42 peptide, have suggested that hydrogen bonding involving Ser26 may be particularly important in organizing a monomer folding nucleus and in subsequent peptide assembly. To study this question, we experimentally determined structure-activity relationships among Aβ42 peptides in which Ser26 was replaced with Gly, Ala, α-aminobutryic acid (Abu), or Cys. We observed that aliphatic substitutions (Ala and Abu) produced substantially increased rates of formation of β-sheet, hydrophobic surface, and fibrils, and higher levels of cellular toxicity. Replacement of the Ser hydroxyl group with a sulfhydryl moiety (Cys) did not have these effects. Instead, this peptide behaved like native Aβ42, even though the hydropathy of Cys was similar to that of Abu and very different from that of Ser. We conclude that H bonding of Ser26 is the factor most important in its contribution to Aβ42 conformation, assembly, and subsequent toxicity.
淀粉样β蛋白（Aβ）组装是阿尔茨海默病中的一个关键过程。阐明这一过程的机制特征被认为对治疗药物的设计和靶向至关重要。对Aβ最具病理学形式的42个残基的Aβ42肽进行的计算研究表明，涉及Ser26的氢键在组织单体折叠核以及随后的肽组装中可能特别重要。为了研究这个问题，我们通过实验确定了Aβ42肽之间的构效关系，其中Ser26被 Gly、Ala、α-氨基丁酸（Abu）或Cys取代。我们观察到脂肪族取代（Ala和Abu）使β-折叠、疏水表面和原纤维的形成速率大幅增加，并且细胞毒性水平更高。用巯基部分（Cys）取代Ser羟基没有这些影响。相反，这种肽的行为类似于天然Aβ42，尽管Cys的亲水性与Abu相似，与Ser非常不同。我们得出结论，Ser26的氢键是其对Aβ42构象、组装及后续毒性贡献中最重要的因素。
