Multiple dimerizing motifs at different locations modulate the dimerization of the syndecan transmembrane domains.

Syndecans (SDCs) are a family of four members of integral membrane proteins, which play important roles in cell-cell interactions. Dimerization/oligomerization generated by transmembrane domains (TMDs) appears to crucially regulate several functional behaviors of all syndecan members. The different levels of protein-protein interactions mediated by Syndecan TMDs may lead to a rather complicated function of Syndecans. The molecular mechanism of the different dimerization tendencies in each type of SDCs remains unclear. Here, the self-assembly process of syndecan TMD homodimers and heterodimers was studied in molecular details by molecular dynamics simulations. Our computational results showed that the SDC2 forms the most stable homodimer, which is consistent with previous experimental results. Detailed analysis suggests that instead of the conserved dimerizing motif G8XXXG12 in all four SDCs involved in homo- and hetero-dimerization of SDCs. The different locations of GXXXA motif affect the stability of SDC dimers. In addition, we found that A3XXXA7 can stabilize the dimerization, making the dimer of SDC2 the most stable among these SDC dimers. Our results shed light on the complex effect of multiple dimerizing motifs on the dimerization of transmembrane domains.