Intrinsic disorder in PRAME and its role in uveal melanoma
Abstract 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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-023-01197-y |
| _version_ | 1797452068513906688 |
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| author | Michael Antonietti David J. Taylor Gonzalez Mak Djulbegovic Guy W. Dayhoff Vladimir N. Uversky Carol L. Shields Carol L. Karp |
| author_facet | Michael Antonietti David J. Taylor Gonzalez Mak Djulbegovic Guy W. Dayhoff Vladimir N. Uversky Carol L. Shields Carol L. Karp |
| author_sort | Michael Antonietti |
| collection | DOAJ |
| description | Abstract 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 |
| first_indexed | 2024-03-09T15:03:25Z |
| format | Article |
| id | doaj.art-dd630e3ef80a43308fdfaf590d5428f7 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-03-09T15:03:25Z |
| publishDate | 2023-08-01 |
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| series | Cell Communication and Signaling |
| spelling | doaj.art-dd630e3ef80a43308fdfaf590d5428f72023-11-26T13:50:18ZengBMCCell Communication and Signaling1478-811X2023-08-0121111310.1186/s12964-023-01197-yIntrinsic disorder in PRAME and its role in uveal melanomaMichael Antonietti0David J. Taylor Gonzalez1Mak Djulbegovic2Guy W. Dayhoff3Vladimir N. Uversky4Carol L. Shields5Carol L. Karp6Bascom Palmer Eye Institute, University of MiamiBascom Palmer Eye Institute, University of MiamiBascom Palmer Eye Institute, University of MiamiDepartment of Chemistry, College of Art and Sciences, University of South FloridaDepartment of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South FloridaOcular Oncology Service, Wills Eye Hospital, Thomas Jefferson UniversityBascom Palmer Eye Institute, University of MiamiAbstract 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 Abstracthttps://doi.org/10.1186/s12964-023-01197-yUveal melanomaIntrinsically disordered proteinDisorder-to-order-transitionPRAMEPReferentially expressed Antigen in Melanoma |
| spellingShingle | Michael Antonietti David J. Taylor Gonzalez Mak Djulbegovic Guy W. Dayhoff Vladimir N. Uversky Carol L. Shields Carol L. Karp Intrinsic disorder in PRAME and its role in uveal melanoma Cell Communication and Signaling Uveal melanoma Intrinsically disordered protein Disorder-to-order-transition PRAME PReferentially expressed Antigen in Melanoma |
| title | Intrinsic disorder in PRAME and its role in uveal melanoma |
| title_full | Intrinsic disorder in PRAME and its role in uveal melanoma |
| title_fullStr | Intrinsic disorder in PRAME and its role in uveal melanoma |
| title_full_unstemmed | Intrinsic disorder in PRAME and its role in uveal melanoma |
| title_short | Intrinsic disorder in PRAME and its role in uveal melanoma |
| title_sort | intrinsic disorder in prame and its role in uveal melanoma |
| topic | Uveal melanoma Intrinsically disordered protein Disorder-to-order-transition PRAME PReferentially expressed Antigen in Melanoma |
| url | https://doi.org/10.1186/s12964-023-01197-y |
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