Figure 6. Proposed model for human IRE1 activation.

In the absence of external stress, IRE1 is pre-assembled into inactive unphosphorylated dimers via the IF1^L interface of the lumenal domain. Kinase domains within the dimer are positioned in a back-to-back (B2B) orientation, which does not allow for phosphorylation. (Gurevich and Gurevich, 2018) ER stress forces dimers to oligomerize via the IF2^L interface, placing the kinase active sites of adjacent dimers in a face-to-face (F2F) orientation that favors trans-autophosphorylation. Here and throughout the figure, the original dimer is shown in solid blue tones while the newly associated dimer is semi-transparent. (Shattil and Newman, 2004) Phosphorylation at the F2F interface results in a partially phosphorylated oligomer, wherein one protomer of each dimer is phosphorylated and one is not. The relative activity of the RNase domains in this state is unknown. (Chung, 2017) At this point, the oligomer may dissociate into partially phosphorylated dimers. (Reich et al., 1997) Another dimer associates with the partially phosphorylated dimer via the second IF2^L interface, catalyzing phosphorylation of the second protomer of the original dimer. Note that this may either occur sequentially, as shown here, or simultaneously with step 2, if multiple dimers assemble into a hexamer or larger oligomer. Phosphorylated IRE1 now has an active RNase domain and dissociates into fully active dimers (Kaufman, 1999). Eventually, dimers are dephosphorylated by phosphatases and return back into the inactive state.