An Intrinsically Disordered Domain Has a Dual Function Coupled to Compartment-Dependent Redox Control

The functio nal role of unstruct ured protein domains is an emergi ng field in the fram e of intr insically disorder ed protei ns. The involvemen t of intr insically disorder ed doma ins (IDD s) in pr otein target ing and biogenesi s proces ses in mitoch ondria is so far not known. Here, we hav e character ized the struct ural/d ynamic and functio nal properties of an IDD of the su lfhydryl oxidase ALR (augmenter of liver reg enerati on) locat ed in the interme mbrane space of mit ochond ria. At varianc e to the unfolded -to-folded structu ral transitio n of several intrinsi cally disorder ed pro teins, neither substrat e recog nition even ts nor redox switch of its s huttle cystei ne pair is linked to any such structu ral chan ge. How ever, this uns tructu red domain per forms a dual function in two cellular compart ments: it acts (i) as a mitoch ondrial target ing signa l in the cytosol and (ii) as a crucial recogn ition site in the disulfid e relay system of interme mbrane sp ace. This doma in provides an exciting new parad igm for ID Ds ensu ring two dist inct function s that are linked to intrace llular orga nelle target ing.