Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma

Abstract

Background: Specific subvariants of uveal melanoma (UM) are associated with increased rates of metastasis compared to other subvariants. BRCA1 (BReast CAncer gene 1)-associated protein-1 (BAP1) is encoded by a gene that has been linked to aggressive behavior in UM. Methods: We evaluated BAP1 for the presence of intrinsically disordered protein regions (IDPRs) and its protein–protein interactions (PPI). We evaluated specific sequence-based features of the BAP1 protein using a set of bioinformatic databases, predictors, and algorithms. Results: We show that BAP1’s structure contains extensive IDPRs as it is highly enriched in proline residues (the most disordered amino acid; p-value < 0.05), the average percent of predicted disordered residues (PPDR) was 57.34%, and contains 9 disorder-based binding sites (ie. molecular recognition features (MoRFs)). BAP1’s intrinsic disorder allows it to engage in a complex PPI network with at least 49 partners (p-value < 1.0 × 10−16). Conclusion: These findings show that BAP1 contains IDPRs and an intricate PPI network. Mutations in UM that are associated with the BAP1 gene may alter the function of the IDPRs embedded into its structure. These findings develop the understanding of UM and may provide a target for potential novel therapies to treat this aggressive neoplasm.

Intrinsic disorder in PRAME and its role in uveal melanoma

“…GEP allows clinicians to group UM into either Class 1 (low-grade metastatic risk) or Class 2 (high-grade metastatic risk) based on their molecular profiles [ 4 ]. Class 1 UM is associated with upregulation of PReferentially expressed Antigen in MElanoma (PRAME), and class 2 UM mutations are associated with mutations or biallelic inactivation of BRCA1 (breast cancer type 1 susceptibility protein)-associated protein 1 (BAP1) [ 5 – 8 ]. The 5-year actuarial rate for metastasis of class 1 PRAME(-), class 1 PRAME( +), class 2 tumors is 0%, 38%, and 71% respectively [ 9 ].…”

LXS196 for Metastatic Uveal Melanoma - finally some progress

“…Generally, plaque brachytherapy is standard for localised disease, with prevention of local recurrence in >95% of cases [1]. Despite these local treatments, up to 50% of patients will develop haematogenous metastasis, particularly those with high-risk genetic profiles [2]. For example, BAP1 (BRCA-1-associated protein) abnormalities have been linked with aggressiveness through incompletely understood pathways [3].…”

Molecular Genomic Insights into Melanoma Associated Proteins PRAME and BAP1

“…In this study we also found that for PRAME, glutamic acid had the highest median percentage of ‘D’ residues, indicating that Glutamic acid might be responsible for promoting disordered regions in PRAME sequences. For BAP1, Proline had the highest median percentage of ‘D’ residues and previous studies have shown that Proline content in BAP1 is more than the average proline content of the entire UniProt database [13].…”

“…These results and connections are essential for better understanding of melanoma pathogenesis; nevertheless, further research is needed to understand how these genetic variants affect the diverse activities of this critical protein. It is unknown how these mutations affect BAP1’s functional proteomics and interactions with additional proteins [13]. The goal of this study is to provide information on the intrinsic regulatory regions that regulate these critical genes in melanoma.…”