Receptor recycling from the plasma membrane surface by endocytosis is essential to signal transduction and nutrient uptake. A significant fraction of receptors in these processes form dimers. Dimerization of identical partners has been thought to promote receptor uptake due to increased affinity of the dimer for the endocytic machinery. But what happens when receptors with substantially different affinities for the endocytic machinery form heterodimers? Evidence from G protein coupled receptors and receptor tyrosine kinases suggests that heterodimerization with strongly internalized receptors can drive significant uptake of receptors that lack strong interactions with the endocytic machinery. However, a systematic biophysical understanding of these effects has yet to be established. Here we investigate the impact of heterodimerization on receptor internalization using a family of engineered model receptors. As expected, we find that dimerization of a weakly internalized receptor with a strongly internalized receptor promotes uptake of the weakly internalized receptor (A-D). However, the effectiveness of this collaboration depends heavily on the relative strengths of internalization of the two receptors in the dimer. Specifically, as the strengths of internalization of the two receptors become more similar, monomers of each receptor compete for space within the crowded environment of coated pits, mutually inhibiting each other’s uptake (E-H). Similarly, as the strength of the dimer bond between the two receptors is successively weakened, competition for limited space within endocytic structures dominates over collaborative uptake. Collectively, these results demonstrate that the impact of heterodimerization on receptor internalization is controlled by a delicate balance between collaborative and competitive mechanisms.

Receptor heterodimerization modulates endocytic uptake through both collaborative and competitive mechanisms

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.