Expanding the Understanding of the Heterogeneous Nature of Melanoma with Bioinformatics and Disorder-based Proteomics

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Bioinformatics, Drug discovery, Genomics, Intrinsically disordered proteins, Melanoma, Precision medicine, Proteomics, Protein-protein interactions, BRAFserine/threonine-protein kinase B-raf, serine/threonine-protein kinase B-raf, CDK4cyclin-dependent kinase 4, cyclin-dependent kinase 4, D2P2Database of Disordered Protein Prediction, Database of Disordered Protein Prediction, EGFRepidermal growth factor receptor, epidermal growth factor receptor, IDPsintrinsically disordered proteins, intrinsically disordered proteins, IDPRsintrinsically disordered protein regions, intrinsically disordered protein regions, IIHintertumor intrapatient heterogeneity, intertumor intrapatient heterogeneity, IPHinterpatient heterogeneity, interpatient heterogeneity, ITHintratumor heterogeneity, intratumor heterogeneity, KEGGKyoto Encyclopedia of Genes and Genomes, Kyoto Encyclopedia of Genes and Genomes, c-KITKit receptor tyrosine kinase, Kit receptor tyrosine kinase, KRASGTPase KRas, GTPase KRas, MAPKmitogen-activated protein kinase, mitogen-activated protein kinase, MEKdual specificity mitogen-activated protein kinase, dual specificity mitogen-activated protein kinase, c-Metc-Met receptor tyrosine kinase, c-Met receptor tyrosine kinase, MITFmicrophthalmia-associated transcription factor, microphthalmia-associated transcription factor, MoRFmolecular recognition feature, molecular recognition feature, NRASGTPase NRas, GTPase NRas, PD-1programmed cell death protein 1, programmed cell death protein 1, PI3Kphosphoinositide 3-kinase, phosphoinositide 3-kinase, PONDRpredictor of natural disordered regions, predictor of natural disordered regions, PTMspost-translational modifications, post-translational modifications, RTKreceptor tyrosine kinase, receptor tyrosine kinase, UniProtuniversal protein resource, universal protein resource

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The past few decades show that incidences of melanoma are on the rise. The risk associated with this disease is an interplay between genetic and host factors and sun exposure. While scientific progress in the treatment of melanoma is remarkable, additional research is needed to improve patient outcomes and to better understand the heterogenous nature of this disease. Fortunately, as the clinical community enters the era of “big data” and personalized medicine, the rise of bioinformatics that stems from recent advances in high throughout profiling of biological information offers potential for innovative treatment options. This study aims to provide an example of the usefulness of bioinformatics and disorder-based proteomics to identify the molecular pathway in melanoma, garner information on selected proteins from this pathway and uncover their intrinsically disordered proteins regions (IDPRs) and investigate functionality implicated in these IDPRs. The present study provides a new look at the melanoma heterogeneity and suggests that, in addition to the well-established genetic heterogeneity of melanoma, there is another level of heterogeneity that lies within the conformational ensembles that stem from intrinsic disorder in melanoma-related proteins. The hope is that these insights will inspire future drug discovery campaigns.

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International Journal of Biological Macromolecules, v. 150, p. 1281-1293