Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes.
Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes.
复制标题
钙耗竭通过破坏bip底物复合物的稳定性挑战内质网的蛋白质平衡。
作者：
Preissler S;Rato C;Yan Y;Perera LA;Czako A;Ron D
后生动物内质网(ER)既是分泌蛋白质成熟的枢纽，又是细胞内钙储存室，促进依赖钙释放的细胞过程。内质网钙耗竭强烈激活未折叠蛋白反应(UPR)。然而，目前尚不清楚内质网钙离子的波动如何影响细胞器蛋白平衡。在这里，我们报告了钙通过增强其对ADP的亲和力来选择性地影响丰富的后生动物ER Hsp70伴侣蛋白Bip的动力学。在充满钙的内质网中，ADP与ATP水解后的双底物复合体的重新结合在自发和辅助伴侣辅助的核苷酸交换过程中都与ATP结合竞争，有利于底物保留。相反，在钙耗竭的内质网中，ADP到ATP交换的相对加速有利于底物的释放。这些发现解释了在钙耗竭的内质网中观察到的某些底物从BIP中快速解离的原因，并提出了一种调节内质网质量控制和将UPR活性与分泌细胞中动员内质网钙的信号偶联的机制。
The metazoan endoplasmic reticulum (ER) serves both as a hub for maturation of secreted proteins and as an intracellular calcium storage compartment, facilitating calcium-release-dependent cellular processes. ER calcium depletion robustly activates the unfolded protein response (UPR). However, it is unclear how fluctuations in ER calcium impact organellar proteostasis. Here, we report that calcium selectively affects the dynamics of the abundant metazoan ER Hsp70 chaperone BiP, by enhancing its affinity for ADP. In the calcium-replete ER, ADP rebinding to post-ATP hydrolysis BiP-substrate complexes competes with ATP binding during both spontaneous and co-chaperone-assisted nucleotide exchange, favouring substrate retention. Conversely, in the calcium-depleted ER, relative acceleration of ADP-to-ATP exchange favours substrate release. These findings explain the rapid dissociation of certain substrates from BiP observed in the calcium-depleted ER and suggest a mechanism for tuning ER quality control and coupling UPR activity to signals that mobilise ER calcium in secretory cells.