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Structural Protein Analysis of Driver Gene Mutations in Conjunctival Melanoma
Mak B Djulbegovic1, Vladimir N Uversky2,3, J William Harbour1
1Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Abstract:
In recent years, there has been tremendous enthusiasm with respect to detailing the genetic basis of many neoplasms, including conjunctival melanoma (CM). We aim to analyze five proteins associated with CM, namely BRAF, NRAS, c-KIT, NF1, and PTEN. We evaluated each protein for its intrinsically disordered protein regions (IDPRs) and its protein-protein interactions (PPI) with the Predictor of Natural Disordered Protein Regions (PONDR®) and the Search Tool for the Retrieval of Interacting Genes (STRING®). Our PONDR® analysis found high levels of IDPRs in all five proteins with mutations linked to CM. The highest levels of IDPRs were in BRAF (45.95%), followed by PTEN (31.76%), NF1 (22.19%), c-KIT (21.82%), and NRAS (14.81%). Our STRING analysis found that each of these five proteins had more predicted interactions then expected (p-value < 1.0 × 10-16). Our analysis demonstrates that the mutations linked to CM likely affected IDPRs and possibly altered their highly complex PPIs. Quantifying IDPRs in BRAF, NRAS, c-KIT, NF1, and PTEN and understanding these protein regions are important processes as IDPRs can be possible drug targets for novel targeted therapies for treating CM.
Insights
This study analyzed intrinsically disordered protein regions (IDPRs) and protein-protein interactions (PPIs) in five key proteins linked to conjunctival melanoma (CM). Findings suggest mutations affect IDPRs and PPIs, offering potential new therapeutic targets for CM.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- Conjunctival melanoma (CM) is a rare eye cancer.
- Understanding the genetic underpinnings of CM is crucial for developing effective treatments.
- Specific proteins like BRAF, NRAS, c-KIT, NF1, and PTEN are implicated in CM development.
Purpose of the Study:
- To analyze intrinsically disordered protein regions (IDPRs) and protein-protein interactions (PPIs) of five proteins associated with conjunctival melanoma (CM).
- To investigate the potential role of IDPRs and altered PPIs in CM pathogenesis.
- To identify potential therapeutic targets for CM based on these protein characteristics.
Main Methods:
- Utilized the Predictor of Natural Disordered Protein Regions (PONDR®) to quantify IDPRs in BRAF, NRAS, c-KIT, NF1, and PTEN.
- Employed the Search Tool for the Retrieval of Interacting Genes (STRING®) to analyze protein-protein interactions (PPIs).
- Correlated the presence of IDPRs and PPIs with known mutations linked to CM.
Main Results:
- All five analyzed proteins (BRAF, PTEN, NF1, c-KIT, NRAS) exhibited significant levels of intrinsically disordered protein regions (IDPRs).
- BRAF showed the highest IDPR content (45.95%), followed by PTEN (31.76%), NF1 (22.19%), c-KIT (21.82%), and NRAS (14.81%).
- STRING analysis revealed that each protein had significantly more predicted interactions than expected (p < 1.0 × 10⁻¹⁶), indicating complex interaction networks.
Conclusions:
- Mutations associated with conjunctival melanoma likely impact the intrinsically disordered protein regions (IDPRs) of these proteins.
- These alterations in IDPRs may lead to changes in complex protein-protein interactions (PPIs), contributing to CM.
- IDPRs in BRAF, NRAS, c-KIT, NF1, and PTEN represent promising targets for developing novel, targeted therapies for conjunctival melanoma.
