ACS Chem Biol. 2023 Aug 18;18(8):1705-1712. doi: 10.1021/acschembio.3c00292. Epub 2023 Aug 4.
Increased O-GlcNAc is a common feature of cellular stress, and the upregulation of this dynamic modification is associated with improved survival under these conditions. Likewise, the heat shock proteins are also increased under stress and prevent protein misfolding and aggregation. We previously linked these two phenomena by demonstrating that O-GlcNAc directly increases the chaperone of certain small heat shock proteins, including HSP27. Here, we examine this linkage further by exploring the potential function of O-GlcNAc on mutants of HSP27 that cause a heritable neuropathy called Charcot-Marie-Tooth type 2 (CMT2) disease. Using synthetic protein chemistry, we prepared five of these mutants bearing an O-GlcNAc at the major site of modification. Upon subsequent biochemical analysis of these proteins, we found that O-GlcNAc has different effects, depending on the location of the individual mutants. We believe that this has important implications for O-GlcNAc and other PTMs in the context of polymorphisms or diseases with high levels of protein mutation.
O-GlcNAc 的增加是细胞应激的一个共同特征，这种动态修饰的上调与这些条件下提高的生存能力有关。同样，热休克蛋白在应激下也会增加，以防止蛋白质错误折叠和聚集。我们之前通过证明 O-GlcNAc 可以直接增加某些小分子热休克蛋白（包括 HSP27）的伴侣，将这两种现象联系起来。在这里，我们通过探索 O-GlcNAc 对 HSP27 突变体的潜在功能来进一步研究这种联系，这些突变体引起一种遗传性神经病，称为 Charcot-Marie-Tooth 型 2 （CMT2）疾病。我们使用合成蛋白质化学方法，制备了五个带有主要修饰位点的 O-GlcNAc 的突变体。随后对这些蛋白质进行生化分析，我们发现 O-GlcNAc 的作用因单个突变体的位置而异。我们认为，这对于 O-GlcNAc 和其他 PTM 在多态性或具有高水平蛋白质突变的疾病中的作用具有重要意义。
