Structure-function relationship and evolutionary history of the human selenoprotein M (SelM) found over-expressed in
Stefano Guariniello1, Giovanni Colonna1, Raffaele Raucci1
1Biochemistry, Biophysics and General Pathology Department and Computational Biology Doctorate, Second University of Naples, Naples, Italy.
Abstract:
In humans we know 25 selenoproteins that play important roles in redox regulation, detoxification, immune-system protection and viral suppression. In particular, selenoprotein M (SelM) may function as thiol disulfide oxidoreductase that participates in the formation of disulfide bonds, and can be implicated in calcium responses. However, it presents a redox motif (CXXU), where U is a selenocysteine, and may also function as redox regulator because its decreased or increased expression regulated by dietary selenium alters redox homeostasis. No data are reported in literature about its involvement in cancer but only in neurodegenerative diseases. In this paper we evaluated the SelM expression in two hepatoma cell lines, HepG2 and Huh7, compared to normal hepatocytes. The results suggested its involvement in hepatocellular carcinoma (HCC) as well as its possible use to follow the progression of this cancer as putative marker. The aim of this study has been to analyze the structure-function relationships of SelM. Hence, firstly we studied the evolutionary history of this protein by phylogenetic analysis and GC content of genes from various species. So, we modeled the three-dimensional structure of the human SelM evaluating its energetic stability by molecular dynamics simulations. Moreover, we modeled some of its mutants to obtain structural information helpful for structure-based drug design.
Insights
Selenoprotein M (SelM) is investigated for its role in liver cancer. Researchers found SelM expression altered in hepatocellular carcinoma, suggesting its potential as a cancer marker and therapeutic target.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Humans possess 25 selenoproteins crucial for redox regulation, detoxification, immune function, and viral suppression.
- Selenoprotein M (SelM), a thiol disulfide oxidoreductase, is involved in disulfide bond formation and calcium responses, with a redox motif (CXXU).
- SelM's expression, modulated by dietary selenium, impacts redox homeostasis, but its role in cancer remains unexplored, with existing research focused on neurodegenerative diseases.
Purpose of the Study:
- To investigate the expression of SelM in hepatocellular carcinoma (HCC) cell lines compared to normal hepatocytes.
- To analyze the structure-function relationships of SelM, including its evolutionary history and structural dynamics.
- To explore the potential of SelM as a biomarker for HCC progression and as a target for structure-based drug design.
Main Methods:
- Phylogenetic analysis and gene GC content analysis to study SelM's evolutionary history.
- Molecular dynamics simulations to model the three-dimensional structure and energetic stability of human SelM.
- Modeling of SelM mutants to gather structural insights for drug design.
Main Results:
- SelM expression was evaluated in HepG2 and Huh7 hepatoma cell lines relative to normal hepatocytes.
- Findings suggest SelM's involvement in hepatocellular carcinoma.
- The study provides structural and evolutionary insights into SelM, potentially aiding in drug development.
Conclusions:
- SelM expression is altered in hepatocellular carcinoma, indicating its potential role in liver cancer.
- SelM may serve as a prognostic marker for HCC progression.
- Structural and evolutionary analyses of SelM offer a foundation for developing targeted therapies.
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