ArticleInternational journal of biological macromolecules2023
Intrinsic disorder may drive the interaction of PROS1 and MERTK in uveal melanoma.
Article in International journal of biological macromolecules, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 13 citations in OpenAlex.
- A Multistep Immune-Competent Genetically Engineered Mouse Model Reveals Phenotypic Plasticity in Uveal Melanoma.Cancer research · 2026Article
- Deep Learning and Experimental Validation of BRCA1-Associated Protein-1 Missense Variant Pathogenicity in Uveal Melanoma.Ophthalmology science · 2026Article
- Bidirectional regulatory mechanisms and therapeutic prospects of tumor hypercoagulable state and immunosuppressive tumor microenvironment.Oncology reviews · 2026Review
- A multi-step immune-competent genetic mouse model reveals phenotypic plasticity in uveal melanoma.bioRxiv : the preprint server for biology · 2025Article
- A Computational Approach to Characterize the Protein S-Mer Tyrosine Kinase (PROS1-MERTK) Protein-Protein Interaction Dynamics.Cell biochemistry and biophysics · 2025Article
- An Analysis of Intrinsic Protein Disorder in Antimicrobial Peptides.The protein journal · 2025Article
- Ovarian expression of MerTK and its ligand Pros1 in non-pregnant estrus and pregnant mice.Journal of molecular histology · 2024Article
- Intrinsic disorder in the human vitreous proteome.International journal of biological macromolecules · 2024Article
- Structural Properties of Rat Intestinal Fatty Acid-Binding Protein with its Dynamics: Insights into Intrinsic Disorder.Protein and peptide letters · 2024Article
- AlphaMissense Predictions and ClinVar Annotations: A Deep Learning Approach to Uveal Melanoma.Ophthalmology scienceArticle
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundClass 2 uveal melanomas are associated with the inactivation of the BRCA1 ((breast cancer type 1 susceptibility protein)-associated protein 1 (BAP1)) gene. Inactivation of BAP1 promotes the upregulation of vitamin K-dependent protein S (PROS1), which interacts with the tyrosine-protein kinase Mer (MERTK) receptor on M2 macrophages to induce an immunosuppressive environment.
methodsWe simulated the interaction of PROS1 with MERTK with ColabFold. We evaluated PROS1 and MERTK for the presence of intrinsically disordered protein regions (IDPRs) and disorder-to-order (DOT) regions to understand their protein-protein interaction (PPI). We first evaluated the structure of each protein with AlphaFold. We then analyzed specific sequence-based features of the PROS1 and MERTK with a suite of bioinformatics tools.
resultsWith high-resolution, moderate confidence, we successfully modeled the interaction between PROS1 and MERTK (predicted local distance difference test score (pDLLT) = 70.68). Our structural analysis qualitatively demonstrated IDPRs (i.e., spaghetti-like entities) in PROS1 and MERK. PROS1 was 23.37 % disordered, and MERTK was 23.09 % disordered, classifying them as moderately disordered and flexible proteins. PROS1 was significantly enriched in cysteine, the most order-promoting residue (p-value <0.05). Our IUPred analysis demonstrated that there are two disorder-to-order transition (DOT) regions in PROS1. MERTK was significantly enriched in proline, the most disorder-promoting residue (p-value <0.05), but did not contain DOT regions. Our STRING analysis demonstrated that the PPI network between PROS1 and MERTK is more complex than their assumed one-to-one binding (p-value <2.0 × 10
conclusionOur findings present a novel prediction for the interaction between PROS1 and MERTK. Our findings show that PROS1 and MERTK contain elements of intrinsic disorder. PROS1 has two DOT regions that are attractive immunotherapy targets. We recommend that IDPRs and DOT regions found in PROS1 and MERTK should be considered when developing immunotherapies targeting this PPI.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.