Structural Protein Analysis of Driver Gene Mutations in Conjunctival Melanoma

Djulbegovic, Mak; Uversky, Vladimir N.; Harbour, J. William; Karp, Carol L.

doi:10.3390/genes12101625

Cited by 9 publications

(3 citation statements)

References 45 publications

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“…Mutations that impact the intrinsic disorder protein regions (IDPRs) have been implicated in developing other neoplasms, including conjunctival melanoma and ocular surface squamous neoplasia [ 35 , 36 , 37 ]. Dysregulation of disordered regions that leads to dysfunction of BAP1 may have a role in the development of UM.…”

Section: Discussionmentioning

confidence: 99%

“…IDPRs are likely to be involved in an array of diverse biological functions [ 32 , 33 , 34 ]. Our group’s previous studies have demonstrated associations between IDPRs and the development of ocular surface squamous neoplasia and conjunctival melanoma [ 35 , 36 , 37 ]. Importantly, in a shift from structure-specific drug discovery campaigns, IDPRs have begun to be targeted to treat various cancers [ 38 , 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

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Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma

Djulbegovic

Taylor

Uversky

et al. 2022

Genes

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma

Djulbegovic

Taylor

Uversky

et al. 2022

Genes

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“…As summarized below, mutations found in CMs often affect the major actors or mediators of these two signaling cascades/pathways. A recent in silico structural analysis of CM-associated proteins in these pathways has revealed highly complex protein−protein interactions, which are predicted to be impacted by CM-linked mutations [ 35 ].…”

Section: Mutations Affecting the Major Actors Or Mediators Of The Map...mentioning

confidence: 99%

Genetic Aspects of Conjunctival Melanoma: A Review

Chang,

Demirci,

Demirci

2023

Genes

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Conjunctival melanoma (CM) is a rare but aggressive cancer. Over the past decade, molecular studies using rapidly advancing technologies have increasingly improved our understanding of CM genetics. CMs are mainly characterized by dysregulated MAPK and PI3K/AKT/mTOR pathways, driven by commonly mutated (BRAF, NRAS, NF1) or less commonly mutated (KIT, PTEN) genes. Another group of genes frequently mutated in CMs include TERT and ATRX, with known roles in telomere maintenance and chromatin remodeling/epigenetic regulation. Uveal melanoma-related genes (BAP1, SF3B1, GNAQ/11) can also be mutated in CMs, albeit infrequently. Additional CM-related mutated genes have increasingly been identified using more comprehensive genetic analyses, awaiting further confirmation in additional/larger studies. As a tumor arising in a partly sun-exposed mucosal tissue, CM exhibits a distinct genomic profile, including the frequent presence of an ultraviolet (UV) signature (and high mutational load) and also the common occurrence of large structural variations (distributed across the genome) in addition to specific gene mutations. The knowledge gained from CM genetic studies to date has led to new therapeutic avenues, including the use of targeted and/or immuno-therapies with promising outcomes in several cases. Accordingly, the implementation of tumor genetic testing into the routine clinical care of CM patients holds promise to further improve and personalize their treatments. Likewise, a growing knowledge of poor prognosis-associated genetic changes in CMs (NRAS, TERT, and uveal melanoma signature mutations and chromosome 10q deletions) may ultimately guide future strategies for prognostic testing to further improve clinical outcomes (by tailoring surveillance and considering prophylactic treatments in patients with high-risk primary tumors).

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Targeting Intrinsically Disordered Proteins (IDPs) in Drug Discovery

Vemulapalli

2024

Computational Methods for Rational Drug Design

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Structural Protein Analysis of Driver Gene Mutations in Conjunctival Melanoma

Cited by 9 publications

References 45 publications

Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma

Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma

Genetic Aspects of Conjunctival Melanoma: A Review

Targeting Intrinsically Disordered Proteins (IDPs) in Drug Discovery

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