Structural analysis of tumor-related single amino acid mutations in human MxA protein
Jia-Li Hu1, Yi-Jun Hua2, Yang Chen3
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, P.R. China. hujl@sysucc.org.cn.
Background:
Human myxovirus resistant protein A (MxA), encoded by the myxovirus resistance 1 (Mx1) gene, is an interferon (IFN)-triggered dynamin-like multi-domain GTPase involved in innate immune responses against viral infections. Recent studies suggest that MxA is associated with several human cancers and may be a tumor suppressor and a promising biomarker for IFN therapy. Mx1 gene mutations in the coding region for MxA have been discovered in many types of cancer, suggesting potential biological associations between mutations in MxA protein and corresponding cancers. In this study, we performed a systematic analysis based on the crystal structures of MxA and elucidated how these mutations specifically affect the structure and therefore the function of MxA protein.
Methods:
Cancer-associated Mx1 mutations were collected and screened from the COSMIC database. Twenty-two unique mutations that cause single amino acid alterations in the MxA protein were chosen for the analysis. Amino acid sequence alignment was performed using Clustal W to check the conservation level of mutation sites in Mx proteins and dynamins. Structural analysis of the mutants was carried out with Coot. Structural models of selected mutants were generated by the SWISS-MODEL server for comparison with the corresponding non-mutated structures. All structural figures were generated using PyMOL.
Results:
We analyzed the conservation level of the single-point mutation sites and mapped them on different domains of MxA. Through individual structural analysis, we found that some mutations severely affect the stability and function of MxA either by disrupting the intra-/inter-molecular interactions supported by the original residues or by incurring unfavorable configuration alterations, whereas other mutations lead to gentle or no interference to the protein stability and function because of positions or polarity features. The potential clinical value of the mutations that lead to drastic influence on MxA protein is also assessed.
Conclusions:
Among all of the reported tumor-associated single-point mutations, seven of them notably affect the structure and function of MxA and therefore deserve more attention with respect to potential clinical applications. Our research provides an example for systematic analysis and consequence evaluation of single-point mutations on a given cancer-related protein.
Insights
Human myxovirus resistant protein A (MxA) mutations impact cancer. This study analyzed 22 mutations, identifying seven that significantly alter MxA structure and function, suggesting potential clinical applications for cancer therapy.
Area of Science:
- Structural biology
- Cancer research
- Immunology
Background:
- Human myxovirus resistant protein A (MxA) is an interferon-induced GTPase crucial for innate immunity.
- MxA is implicated in various cancers, potentially acting as a tumor suppressor and biomarker for interferon therapy.
- Mx1 gene mutations altering MxA are found in numerous cancers, suggesting functional relevance.
Purpose of the Study:
- To systematically analyze cancer-associated Mx1 mutations.
- To elucidate how specific mutations affect MxA protein structure and function.
- To assess the clinical significance of mutations impacting MxA.
Main Methods:
- Collected and screened cancer-associated Mx1 mutations from the COSMIC database.
- Selected 22 unique single amino acid alteration mutations for analysis.
- Performed sequence alignment, structural analysis using Coot, and model generation with SWISS-MODEL.
Main Results:
- Analyzed mutation site conservation and mapped them onto MxA domains.
- Identified mutations that disrupt MxA stability and function by altering interactions or configurations.
- Found other mutations with minimal impact due to their location or polarity.
Conclusions:
- Seven tumor-associated single-point mutations significantly affect MxA structure and function.
- These seven mutations warrant further investigation for potential clinical applications.
- The study provides a framework for analyzing cancer-related protein mutations.
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