Fewell S W, Day B W, Brodsky J L
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
J Biol Chem. 2001 Jan 12;276(2):910-4. doi: 10.1074/jbc.M008535200.
Members of the hsc70 family of molecular chaperones are critical players in the folding and quality control of cellular proteins. Because several human diseases arise from defects in protein folding, the activity of hsc70 chaperones is a potential therapeutic target for these disorders. By using a known hsc70 modulator, 15-deoxyspergualin, as a seed, we identified a novel inhibitor of hsc70 activity. This compound, R/1, inhibits the endogenous and DnaJ-stimulated ATPase activity of hsc70 by 48 and 51%, respectively, and blocks the hsc70-mediated translocation of a preprotein into yeast endoplasmic reticulum-derived microsomal vesicles. Biochemical studies demonstrate that R/1 most likely exerts these effects by altering the oligomeric state of hsc70.
分子伴侣hsc70家族成员是细胞蛋白质折叠和质量控制的关键参与者。由于几种人类疾病源于蛋白质折叠缺陷，hsc70伴侣的活性是这些疾病的潜在治疗靶点。我们以已知的hsc70调节剂15-脱氧精胍菌素为起点，鉴定出一种新型的hsc70活性抑制剂。这种化合物R/1分别抑制hsc70的内源性和DnaJ刺激的ATP酶活性48%和51%，并阻断hsc70介导的前体蛋白转运到酵母内质网衍生的微粒体囊泡中。生化研究表明，R/1很可能通过改变hsc70的寡聚状态来发挥这些作用。
