In many cellular signaling pathways, key components form clusters at the cell membrane. Although much work has focused on the mechanisms behind such cluster formation, the implications for downstream signaling remain poorly understood. Here, motivated by recent experiments, we use particle-based simulation to study a covalent modification network in which the activating component is either clustered or randomly distributed on the membrane. We find that whereas clustering reduces the response of a single-modification network, it can enhance the response of a double-modification network. The reduction is a bulk effect: a cluster presents a smaller effective target to a substrate molecule in the bulk. The enhancement, on the other hand, is a local effect: a cluster promotes the rapid rebinding and second activation of singly activated substrate molecules. As such, the enhancement relies on frequent collisions on a short timescale, leading to an optimal ratio of diffusion to association that agrees with typical measured rates. We complement simulation with analytic results at both the mean-field and first-passage distribution levels. Our results emphasize the importance of spatially resolved models, showing that significant effects of spatial correlations persist even in spatially averaged quantities such as response curves. © 2012 Biophysical Society.
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