Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
FASEB J. 2011 Nov;25(11):3929-37. doi: 10.1096/fj.11-184911. Epub 2011 Aug 10.
Peripheral myelin protein 22 (PMP22) and protein 0 (P0) are major peripheral myelin glycoproteins, and mutations in these two proteins are associated with hereditary demyelinating peripheral neuropathies. Calnexin, calreticulin, and ERp57 are critical components of protein quality control responsible for proper folding of newly synthesized glycoproteins. Here, using confocal microscopy, we show that cell surface targeting of P0 and PMP22 is not affected in the absence of the endoplasmic reticulum chaperones. However, the folding and function (adhesiveness) of PMP22 and P0, measured using the adhesion assay, are affected significantly in the absence of calnexin but not in the absence of calreticulin. Deficiency in oxidoreductase ERp57 results in impaired folding and function of P0, a disulfide bond-containing protein, but does not have any effect on folding or function of PMP22 (a protein that does not contain a disulfide bond). We concluded that calnexin and ERp57, but not calreticulin, play an important role in the biology of peripheral myelin proteins PMP22 and P0, and, consequently, these chaperones may contribute to the pathogenesis of peripheral neuropathies and the diversity of these neurological disorders.
外周髓鞘蛋白 22（PMP22）和蛋白 0（P0）是主要的外周髓鞘糖蛋白，这两种蛋白的突变与遗传性脱髓鞘周围神经病有关。钙连蛋白、钙网蛋白和 ERp57 是负责新合成糖蛋白正确折叠的蛋白质质量控制的关键组成部分。在这里，我们使用共聚焦显微镜显示，在没有内质网伴侣的情况下，P0 和 PMP22 的细胞表面靶向不受影响。然而，使用粘附测定法测量的 PMP22 和 P0 的折叠和功能（粘附性）在缺乏钙连蛋白的情况下受到显著影响，但在缺乏钙网蛋白的情况下不受影响。氧化还原酶 ERp57 的缺乏导致含有二硫键的蛋白 P0 的折叠和功能受损，但对不含二硫键的 PMP22 的折叠或功能没有任何影响。我们得出结论，钙连蛋白和 ERp57（而非钙网蛋白）在外周髓鞘蛋白 PMP22 和 P0 的生物学中发挥重要作用，因此，这些伴侣可能有助于周围神经病的发病机制和这些神经紊乱的多样性。
