It is well known that receptor tyrosine kinases (RTKs), a class of 58 single-pass membrane proteins, signal by forming homodimers. Heterodimers between subfamilies, such as between ERBB1 and ERBB2, are also well known. It was surprising, however, when Jandial and co-workers (2017) showed experimentally that Her2 and TrkB can form heterodimers. TrkB is an RTK located in the neurons and regulates neuronal growth. Her2 is an epidermal growth factor and an oncoprotein. Jandial and co-workers (2017) showed that Her2 and TrkB co-immunoprecipated and colocalized using cells taken from breast cancer patients whose cancer had metastasized to the brain. It is not known how these two proteins dimerize. Although both have a single-pass transmembrane domain and are RTKs, they have very different overall structures, are in different RTK subfamilies, and are ordinarily located in different tissues. Elucidating how they dimerize has clinical implications, and the potential to alter our fundamental understanding of RTK signaling. Here, we explore the hypothesis that TrkB and Her2 dimerization is driven by the transmembrane domains. We use coarse-grained molecular dynamics simulations and an enhanced sampling technique called weighted ensemble that enables spontaneous dimerization, to capture dimeric ensembles and calculate the free energy of dimerization. We report dynamics ensembles and the free energy of dimerization between the transmembrane domains of TrkB and Her2. Our workflow enables studies of the mechanisms of dimerization between TrkB and Her2. Our technique can be applied to other RTK transmembrane dimers and could lead to novel insights into cell signaling.
Ritchie et al. (Sun,) studied this question.