  The endoplasmic reticulum (ER) is a dynamic network of interconnected sheets
and tubules that orchestrates the distribution of lipids, ions, and proteins
throughout the cell. The impact of its complex, dynamic morphology on its
function as an intracellular transport hub remains poorly understood. To
elucidate the functional consequences of ER network structure and dynamics, we
quantify how the heterogeneity of the peripheral ER in COS7 cells affects
diffusive protein transport. In vivo imaging of photoactivated ER membrane
proteins demonstrates their non-uniform spreading to adjacent regions, in a
manner consistent with simulations of diffusing particles on extracted network
structures. Using a minimal network model to represent tubule rearrangements,
we demonstrate that ER network dynamics are sufficiently slow to have little
effect on diffusive protein transport. Furthermore, stochastic simulations
reveal a novel consequence of ER network heterogeneity: the existence of 'hot
spots' where sparse diffusive reactants are more likely to find one another.
Intriguingly, ER exit sites are disproportionately found in these highly
accessible regions. Combining in vivo experiments with analytic calculations,
quantitative image analysis, and computational modeling, we demonstrate how
structure guides diffusive protein transport and reactions in the ER.
