Matrix metalloproteases are known to represent an early step in the evolution of the immune system. Similarly, neutrophil gelatinase-associated lipocalin is known to be a key effector in immune response. MMP-9 interacts with NGAL, but their interaction mechanisms remain unclear. Functional interaction between proteins is ensured by coevolution. Protein coevolution was inferred by calculating the linear correlation coefficients between inter-protein distance matrices using MirrorTree. Among examined mammal species, we found a robust signal of MMP-9/NGAL coevolution exclusively within Primates (R = 0.96, p < 1e-06). Owing to the high conservation of these proteins among Mammals, we chose to utilize a recent version of Blocks in Sequences (BIS2) algorithm implemented in BIS2Analyzer webserver. Coevolution clusters between the two proteins were identified in MMP-9 fibronectin and hemopexin domains. Our results suggest that MMP-9/NGAL interaction is a recent evolutionary acquisition in Primates. Furthermore, MMP-9 hemopexin domain would represent a promising target for drug design against these molecules.

已知基质金属蛋白酶代表免疫系统进化的早期步骤。同样，已知中性粒细胞明胶酶相关的脂质运载蛋白是免疫反应中的关键效应物。MMP-9 与 NGAL 相互作用，但它们的相互作用机制仍不清楚。蛋白质之间的功能相互作用是通过共同进化来确保的。通过使用MirrorTree计算蛋白质间距离矩阵之间的线性相关系数来推断蛋白质协同进化。在检查过的哺乳动物物种中，我们发现了仅在灵长类动物中 MMP-9/NGAL 共同进化的强烈信号（R = 0.96，p  < 1e-06）。由于哺乳动物中这些蛋白质的高度保守性，我们选择使用最新版本的序列块 (BIS2)在BIS2Analyzer网络服务器中实现的算法。在 MMP-9 纤连蛋白和血红素结合蛋白结构域中鉴定了两种蛋白质之间的共同进化簇。我们的结果表明，MMP-9/NGAL 相互作用是灵长类动物最近的进化获得。此外，MMP-9 hemopexin 结构域将代表针对这些分子的药物设计的有希望的目标。