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Updated: Jul 18, 2025
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Intrinsic disorder in PRAME and its role in uveal melanoma
Michael Antonietti1, David J Taylor Gonzalez1, Mak Djulbegovic1
1Bascom Palmer Eye Institute, University of Miami, 900 NW 17th Street, Miami, FL, 33136, USA.
Introduction:
The PReferentially expressed Antigen in MElanoma (PRAME) protein has been shown to be an independent biomarker for increased risk of metastasis in Class 1 uveal melanomas (UM). Intrinsically disordered proteins and regions of proteins (IDPs/IDPRs) are proteins that do not have a well-defined three-dimensional structure and have been linked to neoplastic development. Our study aimed to evaluate the presence of intrinsic disorder in PRAME and the role these structureless regions have in PRAME( +) Class 1 UM.
Methods:
A bioinformatics study to characterize PRAME's propensity for the intrinsic disorder. We first used the AlphaFold tool to qualitatively assess the protein structure of PRAME. Then we used the Compositional Profiler and a set of per-residue intrinsic disorder predictors to quantify the intrinsic disorder. The Database of Disordered Protein Prediction (D2P2) platform, IUPred, FuzDrop, fIDPnn, AUCpred, SPOT-Disorder2, and metapredict V2 allowed us to evaluate the potential functional disorder of PRAME. Additionally, we used the Search Tool for the Retrieval of Interacting Genes (STRING) to analyze PRAME's potential interactions with other proteins.
Results:
Our structural analysis showed that PRAME contains intrinsically disordered protein regions (IDPRs), which are structureless and flexible. We found that PRAME is significantly enriched with serine (p-value < 0.05), a disorder-promoting amino acid. PRAME was found to have an average disorder score of 16.49% (i.e., moderately disordered) across six per-residue intrinsic disorder predictors. Our IUPred analysis revealed the presence of disorder-to-order transition (DOT) regions in PRAME near the C-terminus of the protein (residues 475-509). The D2P2 platform predicted a region from approximately 140 and 175 to be highly concentrated with post-translational modifications (PTMs). FuzDrop predicted the PTM hot spot of PRAME to be a droplet-promoting region and an aggregation hotspot. Finally, our analysis using the STRING tool revealed that PRAME has significantly more interactions with other proteins than expected for randomly selected proteins of the same size, with the ability to interact with 84 different partners (STRING analysis result: p-value < 1.0 × 10-16; model confidence: 0.400).
Conclusion:
Our study revealed that PRAME has IDPRs that are possibly linked to its functionality in the context of Class 1 UM. The regions of functionality (i.e., DOT regions, PTM sites, droplet-promoting regions, and aggregation hotspots) are localized to regions of high levels of disorder. PRAME has a complex protein-protein interaction (PPI) network that may be secondary to the structureless features of the polypeptide. Our findings contribute to our understanding of UM and suggest that IDPRs and DOT regions in PRAME may be targeted in developing new therapies for this aggressive cancer. Video Abstract.
Insights
The PReferentially expressed Antigen in MElanoma (PRAME) protein contains intrinsically disordered regions (IDPRs) linked to its function in Class 1 uveal melanoma (UM). These disordered regions, including disorder-to-order transition zones and post-translational modification sites, may offer new therapeutic targets for UM.
Area of Science:
- Structural bioinformatics and cancer biology.
- Investigating the role of intrinsically disordered proteins in cancer progression.
Background:
- PRAME is a biomarker for metastasis risk in Class 1 uveal melanoma (UM).
- Intrinsically disordered proteins (IDPs) and regions (IDPRs) lack stable 3D structures and are implicated in cancer.
- This study explores the intrinsic disorder of PRAME and its potential role in Class 1 UM.
Discussion:
- PRAME exhibits intrinsically disordered regions (IDPRs), enriched with serine, a disorder-promoting amino acid.
- Functional regions like disorder-to-order transition (DOT) zones and post-translational modification (PTM) hotspots are identified within these disordered regions.
- PRAME possesses a complex protein-protein interaction (PPI) network, potentially driven by its disordered nature.
Key Insights:
- PRAME is moderately disordered (16.49% disorder score) with specific DOT regions (residues 475-509) and PTM hotspots (residues 140-175).
- FuzDrop analysis indicates PRAME's PTM hotspots are also droplet-promoting and aggregation-prone.
- PRAME interacts with significantly more proteins (84 partners) than expected, highlighting its extensive interactome.
Outlook:
- The identified IDPRs, DOT regions, and PTM sites in PRAME are crucial for its function in Class 1 UM.
- Targeting these intrinsically disordered regions could lead to novel therapeutic strategies for uveal melanoma.
- Further research into PRAME's disordered structure and extensive PPI network is warranted for understanding UM pathogenesis.
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