分子伴侣特异性免疫抑制剂15-脱氧精胍菌素的选择性：在不影响DnaJ伴侣相互作用的情况下调节Hsc70 ATP酶活性。

Selectivity of the molecular chaperone-specific immunosuppressive agent 15-deoxyspergualin: modulation of Hsc70 ATPase activity without compromising DnaJ chaperone interactions.

作者信息

Brodsky J L

机构信息

Department of Biological Sciences, University of Pittsburgh, PA 15260, USA. jbrodsky+@pitt.edu

出版信息

Biochem Pharmacol. 1999 Apr 15;57(8):877-80. doi: 10.1016/s0006-2952(98)00376-1.

DOI:10.1016/s0006-2952(98)00376-1

Abstract

The immunosuppressive and cytostatic agent 15-deoxyspergualin (DSG) binds to the Hsc70 class of molecular chaperones with a K(D) = 4 microM. Because Hsc70s represent a diverse group of cellular effectors and because Hsc70 function frequently requires a DnaJ molecular chaperone, the specificity of DSG for different Hsc70s and the ability of DSG to block the productive interaction between an Hsc70 and its DnaJ partner were examined. DSG stimulated the ATPase activity of a mammalian and yeast cytosolic Hsc70 from 20 to 40%, but was unable to elicit such a response in a homologous Hsc70, Binding Protein (BiP), that resides in the lumen of the endoplasmic reticulum. In addition, the DnaJ-stimulated Hsc70 ATPase activity and the DnaJ-mediated release of an unfolded polypeptide from an Hsc70 were unaffected by DSG. These results indicate that Hsc70s exhibit substrate selectivity for DSG and that DSG does not compromise Hsc70 functions that require DnaJs. Thus, the immunosuppressive and cytostatic effects of DSG may be specific for a subset of cellular Hsc70s and confined to DnaJ-independent Hsc70-mediated activities.

摘要

免疫抑制及细胞生长抑制因子15 - 脱氧精胍菌素（DSG）以K(D)=4 microM的解离常数与Hsc70类分子伴侣结合。由于Hsc70代表多种细胞效应器，且Hsc70的功能通常需要DnaJ分子伴侣，因此研究了DSG对不同Hsc70的特异性以及DSG阻断Hsc70与其DnaJ伴侣之间有效相互作用的能力。DSG使哺乳动物和酵母胞质Hsc70的ATP酶活性提高了20%至40%，但对内质网腔中的同源Hsc70、结合蛋白（BiP）却无法引发这种反应。此外，DSG不影响DnaJ刺激的Hsc70 ATP酶活性以及DnaJ介导的未折叠多肽从Hsc70的释放。这些结果表明，Hsc70对DSG表现出底物选择性，且DSG不会损害需要DnaJ的Hsc70功能。因此，DSG的免疫抑制和细胞生长抑制作用可能对细胞Hsc70的一个亚群具有特异性，并局限于不依赖DnaJ的Hsc70介导的活性。