Single-molecule functional anatomy of endogenous HER2-HER3 heterodimers
Byoungsan Choi, Minkwon Cha, Gee Sung Eun, Dae Hee Lee, Seul Lee, Muhammad Ehsan, Pil Seok Chae, Won Do Heo, YongKeun Park, Tae‐Young Yoon
Abstract
Human epidermal growth factor receptors (HERs) are the primary targets of many directed cancer therapies. However, the reason a specific dimer of HERs generates a stronger proliferative signal than other permutations remains unclear. Here, we used single-molecule immunoprecipitation to develop a biochemical assay for endogenously-formed, entire HER2-HER3 heterodimers. We observed unexpected, large conformational fluctuations in juxta-membrane and kinase domains of the HER2-HER3 heterodimer. Nevertheless, the individual HER2-HER3 heterodimers catalyze tyrosine phosphorylation at an unusually high rate, while simultaneously interacting with multiple copies of downstream signaling effectors. Our results suggest that the high catalytic rate and multi-tasking capability make a concerted contribution to the strong signaling potency of the HER2-HER3 heterodimers.