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.

Syndecans（SDC）是整合膜蛋白的四个成员组成的家族，在细胞与细胞的相互作用中起着重要的作用。跨膜结构域（TMD）生成的二聚/低聚似乎至关重要地调节了所有syndecan成员的几种功能行为。Syndecan TMDs介导的蛋白质-蛋白质相互作用的不同水平可能导致Syndecans的功能相当复杂。每种类型的SDC中不同二聚化趋势的分子机制仍不清楚。在这里，通过分子动力学模拟，详细研究了Syndecan TMD同二聚体和异二聚体的自组装过程。我们的计算结果表明，SDC2形成最稳定的同型二聚体，这与以前的实验结果是一致的。详细的分析表明，在参与SDC均二聚和异源二聚化的所有四个SDC中，保守的二聚化基序G8XXXG12都不存在。GXXXA基序的不同位置会影响SDC二聚体的稳定性。此外，我们发现A3XXXA7可以稳定二聚化，使SDC2的二聚体在这些SDC二聚体中最稳定。我们的结果揭示了多个二聚化基序对跨膜结构域二聚化的复杂作用。