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Elife ; 92020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33295873

RESUMO

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.


Assuntos
Cálcio/deficiência , Retículo Endoplasmático/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteostase , Difosfato de Adenosina/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Células CHO , Cálcio/metabolismo , Cricetulus , Cristalografia por Raios X , Drosophila , Escherichia coli , Citometria de Fluxo , Proteínas de Choque Térmico HSP70/metabolismo , Imunoprecipitação , Resposta a Proteínas não Dobradas
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