Multiple Dimerizing Motifs 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) appear to crucially regulate several functional behaviors of all syndecan members. The distinct hierarchy of protein-protein interactions mediated by the syndecan TMDs may give rise to considerable complexity in the functions 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 while the SDC1 TMD dimerizes weakly, 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 G3XXXA7 motif in SDC1 competes with the interface of G8XXXG12 and thus disturbs the SDC1 involved dimerization. The SDC3 which contains a G9XXXA13 motif, however, forms a more stable dimer than SDC1, indicating the complexity of the competing effect of the GXXXA motif. As GXXXG and GXXXA are two common sequence motifs in the dimerization of helices, our results shed light on the competing effect of multiple dimerizing motifs on the dimerization of transmembrane domains.