Structural Investigation of Human Prolactin Receptor Transmembrane Domain Homodimerization in a Membrane Environment through Multiscale Simulations.

It is well established that prolactin (PRL) and its receptor (PRLR) are associated with hundreds of biological functions. They have been postulated to be linked to breast and prostate cancers, and PRLR signaling has attracted considerable medical and pharmaceutical interest in the development of compounds targeting PRLR. Dimerization of the receptor through its transmembrane (TM) domain is a key step for understanding its signaling and related issues. Our multiscale simulation results revealed that its TM domain can form dimers in a membrane environment with distinct states stabilized by different residue motifs. On the basis of the simulated data, an activation mechanism of PRL with the importance of two symmetrical tryptophan residues was proposed in detail to determine the conformational change of its receptor, which is essential for signal transduction. The better knowledge of PRLR structure and its protein-protein interaction can considerably contribute to a further understanding of PRLR signaling action and thereby help to develop some new PRLR signaling-based strategies for PRL-related diseases.