Structural characterisation of inhibitory and non-inhibitory MMP-9–TIMP-1 complexes and implications for regulatory mechanisms of MMP-9

Abstract

MMP-9 plays a number of important physiological functions but is also responsible for many pathological processes, including cancer invasion, metastasis, and angiogenesis. It is, therefore, crucial to understand its enzymatic activity, including activation and inhibition mechanisms. This enzyme may also be partially involved in the “cytokine storm” that is characteristic of COVID-19 disease (SARS-CoV-2), as well as in the molecular mechanisms responsible for lung fibrosis. Due to the variety of processing pathways involving MMP-9 in biological systems and its uniqueness due to the O-glycosylated domain (OGD) and fibronectin-like (FBN) domain, specific interactions with its natural TIMP-1 inhibitor should be carefully studied, because they differ significantly from other homologous systems. In particular, earlier experimental studies have indicated that the newly characterised circular form of a proMMP-9 homotrimer exhibits stronger binding properties to TIMP-1 compared to its monomeric form. However, molecular structures of the complexes and the binding mechanisms remain unknown. The purpose of this study is to fill in the gaps in knowledge. Molecular modelling methods are applied to build the inhibitory and non-inhibitory MMP-9–TIMP-1 complexes, which allows for a detailed description of these structures and should allow for a better understanding of the regulatory processes in which MMP-9 is involved.

MMP-9/BDNF ratio predicts more severe COVID-19 outcomes

“…MMP-9 activates signalling molecules such as cytokines or chemokines thus contributing to the development of "cytokine storm" in COVID- 19. In progressive pathological processes, it aggravates activity during degradation and regeneration of the extracellular matrix, with a particularly potent influence on vascular remodelling [11]. Furthermore, by cleaving the chains of many regulatory pro-peptide molecules, MMP-9 facilitates the release of operative, mature forms of peptides.…”

PEGylation of Metal Oxide Nanoparticles Modulates Neutrophil Extracellular Trap Formation

“…Similar TIMP-1 mediated phenomena have been observed in pancreatic and breast cancer [ 128 , 134 ]. Neutrophils possess a matrix metalloproteinase (MMP) known as MMP9, which can form a non-inhibitory complex with TIMP-1, despite the latter being an MMP inhibitor [ 135 ]. While the functional significance of this complex is unclear, it is conceivable that it is functionally analogous to the interaction between TIMP-2 and MMP2, which ultimately results in the activation of MMP2 via other MMPs that subsequently interact with this complex [ 136 ].…”

Investigation of the Possible Protective Effect of N-Acetylcysteine (NAC) against Irinotecan (CPT-11)-Induced Toxicity in Rats

“…They exert their inhibitory effects by non-specifically binding to MMPs [ 48 ]. Therefore, changes in MMP and TIMP levels determine the effectiveness of MMPs in contributing to tissue homeostasis [ 49 ]. Significant changes were detected in the levels of MMP-1, -2, -8 and TIMP-1, both in the blood serum as a reflection of the systemic response and in the hepatorenal and gastrointestinal tract tissues of animals treated with CPT-11.…”