Exploring the Regulatory Function of NGAL in MMP-9 Complexes

Matrix metalloproteinase 9 (MMP-9) is an enzyme involved in the degradation of the extracellular matrix and in numerous physiological and pathological processes. One of the less understood regulatory mechanisms of MMP-9 is its interaction with neutrophil gelatinase-associated lipocalin (NGAL), leading to the formation of a covalent or noncovalent complex, which may affect the enzyme's activity, its stability, and binding by tissue inhibitors of metalloproteinases (TIMPs), in particular TIMP-1. In this study, molecular modeling was used to investigate the structural basis of NGAL's regulatory effect. Covalent and noncovalent MMP-9/NGAL complexes were constructed and analyzed, as well as the tetrameric inhibitory complex MMP-9/NGAL/TIMP-1/MMP-9. Results indicate that NGAL stabilizes the structure of the hemopexin domain of MMP-9, protecting it from autodegradation. Furthermore, the identified protein interactions may explain the experimentally observed increased affinity of TIMP-1 for the MMP-9/NGAL complex. Comparison with the terminal MMP-9/TIMP-1 complex shows that the presence of NGAL induces slight but reproducible changes in the inhibitory interfaces.