Effects of Mutations on Structure–Function Relationships of Matrix Metalloproteinase-1

Singh, Warispreet; Fields, Gregg B.; Christov, Christo; Karabencheva‐Christova, Tatyana G.

doi:10.3390/ijms17101727

Cited by 14 publications

(13 citation statements)

References 31 publications

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“…40 The DCCA is used to visualize which residues play a role in correlated motions that occur between different components of the protein structure. 41 The level of correlation between each Cα atom can be quantified and visualized on a plot, with correlations ranging from +1 to −1, indicating a strong positive to a negative correlation. This allows the identification of regions in the protein, showing correlated motion in the simulation.…”

Section: Methodsmentioning

confidence: 99%

Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase

et al. 2018

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Many natural organic compounds with pharmaceutical applications, including antibiotics (chlortetracycline and vancomycin), antifungal compounds (pyrrolnitrin), and chemotherapeutics (salinosporamide A and rebeccamycin) are chlorinated. Halogenating enzymes like tryptophan 7-halogenase (PrnA) and tryptophan 5-halogenase (PyrH) perform regioselective halogenation of tryptophan. In this study, the conformational dynamics of two flavin-dependent tryptophan halogenases—PrnA and PyrH—was investigated through molecular dynamics simulations, which are in agreement with the crystallographic and kinetic experimental studies of both enzymes and provide further explanation of the experimental data at an atomistic level of accuracy. They show that the binding sites of the cofactor-flavin adenine dinucleotide and the substrate do not come into close proximity during the simulations, thus supporting an enzymatic mechanism without a direct contact between them. Two catalytically important active site residues, glutamate (E346/E354) and lysine (K79/K75) in PrnA and PyrH, respectively, were found to play a key role in positioning the proposed chlorinating agent, hypochlorous acid. The changes in the regioselectivity between PrnA and PyrH arise as a consequence of differences in the orientation of substrate in its binding site.

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Section: Methodsmentioning

confidence: 99%

Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase

et al. 2018

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“…A Transwell experiment ( Wang 2018 ) proved that when the MMP1 gene was silenced, the invasion and migration ability of BRCA was significantly reduced. In addition, collagen is also an important part of ECM ( Ma et al, 2016 ), while MMP1 can degrade type I, II and III collagen ( Singh et al, 2016 ). This study confirmed that MMP1 participated in collagen metabolism and the degradation of extracellular matrix tissue, promoting cancer metastasis.…”

Section: Discussionmentioning

confidence: 99%

Landscape Analysis of Matrix Metalloproteinases Unveils Key Prognostic Markers for Patients With Breast Cancer

Cheng

Chen

et al. 2022

Front. Genet.

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Breast cancer (BRCA) is the most common cancer in the world, of which incidence rate and mortality are the highest in women. Being responsible for the remodeling and degradation of extracellular matrix proteins, matrix metalloproteinases (MMPs) have been regarded as one of the most important protease family related to tumorigenesis. It has been demonstrated that MMPs play crucial roles in some tumor invasion and metastasis. However, the potential roles of MMPs in tumorigenesis and progression of BRCA and its subtype remain elusive. Herein, we conducted a systematic study on MMPs via a series of database-based retrospective analysis, including TCGA, R Studio, GEPIA, Kaplan-Meier Plotter, cBioPortal, STRING, GeneMANIA and TIMER. As a result, many MMP family members were differentially expressed in patients with BRCA, e.g., the expressions of MMP1, MMP9, MMP11 and MMP13 were up-regulated, whereas the expression levels of MMP19 and MMP28 were down-regulated. MMP9, MMP12, MMP15 and MMP27 were significantly correlated with the clinical stages of BRCA, implying their important roles in the occurrence and development of BRCA. In addition, the survival analysis indicated that different expression pattern of MMPs exhibited distinct outcomes in patient with BRCA, e.g., patients with high expression of MMP2, MMP8, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26 and MMP27 had a prolonged survival time, while the others (MMP1, MMP7, MMP9, MMP12 and MMP15) exhibited poor prognosis. Subsequent functional and network analysis revealed MMPs were mainly correlated with parathyroid hormone synthesis and secretion pathway, collagen metabolism, and their effect on the activities of serine hydrolase, serine peptidase and aminopeptidase. Notably, our analysis showed that the expression of MMPs was significantly correlated with the infiltration of various immune cells in BRCA, including CD8+T cells, CD4+T cells, macrophages, neutrophils, B cells, and dendritic cells, suggesting the close correlations between MMPs and immune functions. In short, our study disclosed MMPs play multiple biological roles in the development of BRCA, MMP1 and MMP9 might be used as independent prognostic markers and potential therapeutic targets for diagnosis and treatment for patients with BRCA.

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“…The MMPs are considered the most important proteolytic enzymes in tumor invasion and metastasis, especially MMP-9 [19]. The MMP-9 promotes tumor invasion and metastasis through two mechanisms: by degrading ECM and the basal plasma membrane of the vascular wall, and by promoting capillary angiogenesis of the tumor [20]. It was found that there are binding sites for transcription factors such as NF-κB in the promoter region of human MMP-9.…”

Section: Discussionmentioning

confidence: 99%

Semen affects the biological behavior of HeLa cells by altering ERK signaling

Zhang

Pang

Wang

et al. 2020

aoms

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The aim of the study was to investigate the effects of human semen on the proliferation, survival, migration and invasion of HeLa cervical cancer cells by analyzing the extracellular regulated protein kinase (ERK) pathway. Material and methods: HeLa cells were stimulated with different concentrations of human semen. MTT assay was used to analyze the effects on cell proliferation. Apoptosis in the different experimental groups was quantified by Annexin V-FITC/PI staining. The effect of seminal plasma on in vitro invasiveness of cells was evaluated using transwell assay. Western blotting was used to evaluate ERK pathway activation. Results: Human semen promoted HeLa cell proliferation; ERK1/2 phosphorylation and c-myc expression also increased with increasing semen concentration. U0126 inhibited semen-induced ERK1/2 phosphorylation, c-myc upregulation and cell proliferation. Compared with the control group, semen did not significantly affect the apoptotic rate of HeLa cells (p > 0.05). The transwell assays showed that compared with the control group, the number of invading cells increased significantly with increasing semen concentration, and the difference was significant (p < 0.05) when 1 : 50 semen was added, suggesting that semen promotes the invasion of cervical cancer cells. Western blotting indicated that ERK1/2 phosphorylation began to increase when 1 : 100 semen was added; with increasing semen concentration, ERK1/2 phosphorylation was significantly up-regulated, and the expression of its downstream target gene, c-myc, was also up-regulated (p < 0.05). Conclusions: Semen promoted the proliferation of HeLa cells by activating the ERK pathway and showed increased tumorigenic potential in vivo. Human seminal plasma might be a potential factor contributing to the development of cervical cancer.

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Effects of Mutations on Structure–Function Relationships of Matrix Metalloproteinase-1

Cited by 14 publications

References 31 publications

Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase

Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase

Landscape Analysis of Matrix Metalloproteinases Unveils Key Prognostic Markers for Patients With Breast Cancer

Semen affects the biological behavior of HeLa cells by altering ERK signaling

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