Schematic of the effects of lumenal calcium depletion on availability of PDI1A to fuel client protein oxidation in the ER. In the calcium replete ER, PDI1A is free to engage in oxidative protein folding by shuttling electrons from reduced client protein (client proteinred) to terminal acceptors (via ER oxidases, such as ERO1 and PRDX4) and oxidation (to client proteinox) competes favorably with reduction (exemplified by the action of ERdj5). In the calcium depleted ER, PDI1A is sequestered in a low mobility complex with the abundant chaperone calreticulin, compromising its availability to power the oxidative limb of the ER. The reductive limb, mediated by ERdj5, is unaffected by calcium depletion. The net result is a shift in the balance of the calcium-depleted ER towards a more reduced poise. ER, endoplasmic reticulum; PDI1A, protein disulfide isomerase 1A.