Tube geometry controls protein cluster conformation and stability on the endoplasmic reticulum surface

Abstract

The endoplasmic reticulum (ER), a cellular organelle that forms a cell-spanning network of tubes and sheets, is an important location of protein synthesis and folding. When the ER experiences sustained unfolded protein stress, IRE1 proteins embedded in the ER membrane activate and assemble into clusters as part of the unfolded protein response (UPR). We use kinetic Monte Carlo simulations to explore IRE1 clustering dynamics on the surface of ER tubes. While initially growing clusters are approximately round, once a cluster is sufficiently large a shorter interface length can be achieved by ‘wrapping’ around the ER tube. A wrapped cluster can grow without further interface length increases. Relative to wide tubes, narrower tubes enable cluster wrapping at smaller cluster sizes. Our simulations show that wrapped clusters on narrower tubes grow more rapidly, evaporate more slowly, and require a lower protein concentration to grow compared to equal-area round clusters on wider tubes. These results suggest that cluster wrapping, facilitated by narrower tubes, could be an important factor in the growth and stability of IRE1 clusters and thus impact the persistence of the UPR, connecting geometry to signaling behavior. This work is consistent with recent experimental observations of IRE1 clusters wrapped around narrow tubes in the ER network.