Internalization of receptors from the cell surface regulates diverse physiological processes from the rate of nutrient uptake to the timescale of signaling events. Specifically, cells tune the number of receptors on their surfaces by balancing the rate of receptor delivery with the rate of receptor uptake by endocytosis. The established view is that internalization of receptors is individually controlled by specific biochemical binding interactions. However, work from several groups has suggested that the internalization machinery is saturable by high levels of receptor expression, an effect which has the potential to couple internalization of one receptor to internalization of other receptors present on the cell surface. Specifically, how might the uptake of an individual receptor be impacted by uptake of other receptors that compete with it for limited space within endocytic structures? Here we show that the expression of competing receptors substantially alters the uptake of a model receptor. In particular, endocytic uptake of the model receptor decreased as the number, size, and affinity of its competitors increased (A-C). These competitive effects were well described by an equilibrium thermodynamic model in which the entropic cost of confining receptors within endocytic vesicles was paid by the reduction in free energy associated receptors binding endocytic structures (D,E). This work creates a framework for predicting the impact of competition on receptor recycling by endocytosis. In particular, understanding the physiochemical mechanism behind this competition is critical for predicting receptor uptake in settings where endocytic machinery approaches saturation, as is frequently the case in cancerous cells, which overexpress multiple receptor species associated with tumor growth and metastasis.

Molecular thermodynamics of receptor competition for uptake by endocytosis

2019 Spring National Meeting

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