Single-molecule functional anatomy of endogenous HER2-HER3 heterodimers

• Main Authors: 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
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2020-04-01
• Series: eLife
• Subjects: receptor tyrosine kinase; protein interaction; tyrosine phosphorylation; catalytic rate
• Online Access: https://elifesciences.org/articles/53934

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.