Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, Gdańsk 80-308, Poland.
Intercollegiate Faculty of Biotechnology of UG and MUG, ul. Abrahama 58, Gdańsk 80-307, Poland.
Glycobiology. 2021 Aug 7;31(7):772-786. doi: 10.1093/glycob/cwab016.
A proliferation-inducing ligand (APRIL) is a member of the tumor necrosis factor superfamily. APRIL is quite unique in this superfamily for at least for two reasons: (i) it binds to glycosaminoglycans (GAGs) via its positively charged N-terminus; (ii) one of its signaling receptor, the transmembrane activator and CAML interactor (TACI), was also reported to bind GAGs. Here, as provided by biochemical evidences with the use of an APRIL deletion mutant linked to computational studies, APRIL-GAG interaction involved other regions than the APRIL N-terminus. Preferential interaction of APRIL with heparin followed by chondroitin sulfate E was confirmed by in silico analysis. Both computational and experimental approaches did not reveal the heparan sulfate binding to TACI. Together, computational results corroborated experiments contributing with atomistic details to the knowledge on this biologically relevant trimolecular system. Additionally, a high-throughput rigorous analysis of the free energy calculations data was performed to critically evaluate the applied computational methodologies.
增殖诱导配体 (APRIL) 是肿瘤坏死因子超家族的成员。APRIL 在这个超家族中非常独特，至少有两个原因：(i) 它通过其带正电荷的 N 端与糖胺聚糖 (GAG) 结合；(ii) 其信号受体之一，跨膜激活剂和钙调蛋白相互作用因子 (TACI)，也被报道与 GAG 结合。在这里，通过使用与计算研究相关的 APRIL 缺失突变体提供的生化证据，APRIL-GAG 相互作用涉及 APRIL N 端以外的其他区域。通过计算机分析证实了 APRIL 与肝素的优先相互作用，然后是硫酸软骨素 E。计算和实验方法都没有揭示肝素结合到 TACI。总之，计算结果证实了实验，为这个具有生物学意义的三分子系统提供了原子细节。此外，对自由能计算数据进行了高通量严格分析，以批判性地评估应用的计算方法。
