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Molecular dynamic study on PTEN frameshift mutations in breast cancer provide c2 domain as a potential biomarker
Rohit Karn1, Isaac Arnold Emerson1
1Bioinformatics Programming Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT, Vellore, India.
Abstract:
PTEN is a tumour suppressor gene known for regulating apoptosis, cell growth, and many other pathways. It is one of the most frequently mutated genes comprising the phosphatase domain (PD) and C terminal domain (C2). Direct therapeutic methods are not applicable for targeting PTEN because once gets mutated, it needs restoration. For mutant detection and restoration using PTEN mRNA there is a need to explore various mutations taking place in PTEN, identify their particular domains, and study their interactions within the cellular system. Here, we have tried to highlight a few such regions in the mutated PTEN of breast cancer patients. In this study, we have selected the top-most-occurring PTEN mutation in breast cancer and compared them to determine the specific properties of each mutation and its effect on functionality. Molecular dynamic simulation for 50 ns was performed on five structures to compare the structural behaviour of mutated PTEN in the system. Our finding suggests that frameshift mutations are more damaging and affect the c2 domain. Frameshift mutant fs_ACTT is the highest occurring as well as the most damaging mutation in all the compared structures. Docking study shows that substitution mutations D92H and R130Q causes loss of binding ability towards PIP2 in normal PTEN, interfering the dephosphorylation process. Overall, the C2 domain is more frequently mutated, and the amino acid residues in the C2 domain show more fluctuations compared to the other regions. Our study can provide the basis for selecting frequently mutated C2 domain as a potential therapeutic marker.Communicated by Ramaswamy H. Sarma.
Insights
PTEN mutations in breast cancer are common, with frameshift mutations in the C2 domain being most damaging. Understanding these PTEN mutations can guide therapeutic strategies for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- PTEN is a crucial tumor suppressor gene regulating cell growth and apoptosis.
- Mutations in PTEN, particularly in its phosphatase (PD) and C-terminal (C2) domains, are frequent in various cancers, including breast cancer.
- Restoring PTEN function is essential, necessitating detailed analysis of mutation types and their cellular impact.
Purpose of the Study:
- To investigate and characterize common PTEN mutations in breast cancer patients.
- To compare the functional effects of different PTEN mutations.
- To identify specific PTEN domains and mutations as potential therapeutic targets.
Main Methods:
- Selection of top-occurring PTEN mutations in breast cancer.
- Molecular dynamic simulations (50 ns) to analyze structural behavior of mutated PTEN.
- Molecular docking studies to assess binding affinity, specifically for PIP2 interaction.
Main Results:
- Frameshift mutations in PTEN are more detrimental and predominantly affect the C2 domain.
- The frameshift mutant fs_ACTT was identified as the most frequent and damaging mutation.
- Substitution mutations D92H and R130Q disrupt PIP2 binding, impairing PTEN's dephosphorylation activity.
- The C2 domain exhibits higher mutation frequency and increased amino acid residue fluctuations.
Conclusions:
- The C2 domain is a hotspot for PTEN mutations in breast cancer.
- Frameshift mutations, especially fs_ACTT, significantly impact PTEN function.
- PTEN mutations affecting PIP2 binding highlight mechanisms of tumor suppression loss.
- The C2 domain's frequent mutation and instability suggest its potential as a therapeutic marker for breast cancer.
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