Sam-Sam Association Between EphA2 and SASH1: In Silico Studies of Cancer-Linked Mutations
Marian Vincenzi1, Flavia Anna Mercurio1, Ida Autiero1
1Institute of Biostructures and Bioimaging, National Research Council of Italy, Via Pietro Castellino 111, 80131 Naples, Italy.
Abstract:
Recently, SASH1 has emerged as a novel protein interactor of a few Eph tyrosine kinase receptors like EphA2. These interactions involve the first N-terminal Sam (sterile alpha motif) domain of SASH1 (SASH1-Sam1) and the Sam domain of Eph receptors. Currently, the functional meaning of the SASH1-Sam1/EphA2-Sam complex is unknown, but EphA2 is a well-established and crucial player in cancer onset and progression. Thus, herein, to investigate a possible correlation between the formation of the SASH1-Sam1/EphA2-Sam complex and EphA2 activity in cancer, cancer-linked mutations in SASH1-Sam1 were deeply analyzed. Our research plan relied first on searching the COSMIC database for cancer-related SASH1 variants carrying missense mutations in the Sam1 domain and then, through a variety of bioinformatic tools and molecular dynamic simulations, studying how these mutations could affect the stability of SASH1-Sam1 alone, leading eventually to a defective fold. Next, through docking studies, with the support of AlphaFold2 structure predictions, we investigated if/how mutations in SASH1-Sam1 could affect binding to EphA2-Sam. Our study, apart from presenting a solid multistep research protocol to analyze structural consequences related to cancer-associated protein variants with the support of cutting-edge artificial intelligence tools, suggests a few mutations that could more likely modulate the interaction between SASH1-Sam1 and EphA2-Sam.
Insights
Cancer-associated mutations in SASH1 sterile alpha motif 1 (SASH1-Sam1) may alter its interaction with EphA2 receptor tyrosine kinase. This study analyzes how these mutations affect SASH1-Sam1 stability and binding to EphA2, potentially impacting cancer progression.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- SASH1 protein interacts with Eph tyrosine kinase receptors, including EphA2.
- The sterile alpha motif domain 1 (Sam1) of SASH1 is involved in this interaction.
- EphA2 plays a critical role in cancer development and progression.
Purpose of the Study:
- To investigate the functional consequences of cancer-associated SASH1-Sam1 mutations.
- To determine how these mutations affect SASH1-Sam1 stability and its interaction with EphA2-Sam.
- To explore the potential link between SASH1-Sam1/EphA2-Sam complex formation and EphA2 activity in cancer.
Main Methods:
- Analysis of cancer-related SASH1 variants from the COSMIC database.
- Bioinformatic tools and molecular dynamic simulations to assess SASH1-Sam1 stability.
- AlphaFold2 structure prediction and molecular docking to study SASH1-Sam1/EphA2-Sam binding.
- Computational analysis of missense mutations within the SASH1-Sam1 domain.
Main Results:
- Identified cancer-linked missense mutations in the SASH1-Sam1 domain.
- Simulations predicted that certain mutations could destabilize SASH1-Sam1 structure.
- Docking studies suggested that mutations may alter the binding affinity between SASH1-Sam1 and EphA2-Sam.
- A computational protocol was established for analyzing cancer-associated protein variants.
Conclusions:
- Cancer-associated mutations in SASH1-Sam1 can potentially disrupt its structural integrity.
- These mutations may modulate the interaction with EphA2, influencing EphA2 activity in cancer.
- The study provides a framework for analyzing structural impacts of cancer variants using AI tools.
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