Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma.

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\u27s structure contains extensive IDPRs as it is highly enriched in proline residues (the most disordered amino acid; p-value \u3c 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\u27s intrinsic disorder allows it to engage in a complex PPI network with at least 49 partners (p-value \u3c 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

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\u27s 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 \u3c 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 \u3c 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

The Aqueous Humor Proteome is Intrinsically Disordered

• Our study demonstrated that intrinsic disorder is abundant in the aqueous humor. • The 749 aqueous proteins analyzed were enriched with disorder-promoting residues. • 208 aqueous humor proteins were predicted to be highly intrinsically disordered. • Misregulation of IDPs may promote pathology in the aqueous humor. • IDPs in aqueous humor may serve as future targets for novel therapeutics

Ferroptosis – An Iron- and Disorder-dependent Programmed Cell Death

Programmed cell death (PCD) is an integral component of both developmental and pathological features of an organism. Recently, ferroptosis, a new form of PCD that is dependent on reactive oxygen species and iron, has been described. As with apoptosis, necroptosis, and autophagy, ferroptosis is associated with a large set of proteins assembled in protein-protein interaction (PPI) networks, interactability of which is driven by the presence of intrinsically disordered proteins (IDPs) and IDP regions (IDPRs). Previous investigations have identified the prevalence and functionality of IDPs/IDPRs in non-ferroptosis PCD. The intrinsic disorder in protein structures is used to increase the regulatory powers of these processes. As uncontrolled PCD is associated with the onset of various pathological traits, uncovering the association between intrinsic disorder and ferroptosis-related proteins is crucial. To understand this association, 31 human ferroptosis-related proteins were analyzed via a multi-dimensional array of bioinformatics and computational techniques. In addition, a disorder meta-predictor (PONDR® FIT) was implored to look at the evolutionary conservation of intrinsic disorder in these proteins. This study presents evidence that IDPs and IDPRs are prevalent in ferroptosis. The intrinsic disorder found in ferroptosis has far-reaching functional implications related to ferroptosis-related PPIs and molecular interactions

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

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

Theoretical Study of the Effect of Halogen Substitution in Molecular Porous Materials for CO\u3csub\u3e2\u3c/sub\u3e and C\u3csub\u3e2\u3c/sub\u3eH\u3csub\u3e2\u3c/sub\u3e Sorption

Grand canonical Monte Carlo (GCMC) simulations of carbon dioxide (CO2) and acetylene (C2H2) sorption were performed in MPM-1-Cl and MPM-1-Br, two robust molecular porous materials (MPMs) that were synthesized by the addition of adenine to CuX2 (X = Cl or Br) by solvent diffusion. Previous experimental studies revealed that both MPMs are selective for C2H2 over CO2 [Xie DY, et al. (2017) CIESC J 68: 154–162]. Simulations in MPM-1-Cl and MPM-1-Br were carried out using polarizable and nonpolarizable potentials of the respective sorbates; this was done to investigate the role of explicit induction on the gas sorption mechanism in these materials. The calculated sorption isotherms and isosteric heat of adsorption (Qst) values for both sorbates are in reasonable agreement with the corresponding experimental measurements, with simulations using the polarizable models producing the closest overall agreement. The modeled CO2 binding site in both MPMs was discovered as sorption between the halide ions of two adjacent [Cu2(adenine)4X2]2+ (X = Cl, Br) units. In the case of C2H2, it was found that the sorbate molecule prefers to align along the X–Cu–Cu–X axis of the copper paddlewheels such that each H atom of the C2H2 molecule can interact favorably with the coordinated X− ions. The simulations revealed that both MPMs exhibit stronger interactions with C2H2 than CO2, which is consistent with experimental findings. The effect of halogen substitution toward CO2 and C2H2 sorption in two isostructural MPMs was also elucidated in our theoretical studies

Theoretical study of the effect of halogen substitution in molecular porous materials for CO₂ and C₂H₂ sorption

Grand canonical Monte Carlo (GCMC) simulations of carbondioxide (CO$_2$) and acetylene (C$_2$H$_2$) sorption were performed in MPM-1-Cl and MPM-1-Br, two robust molecular porous materials (MPMs) that were synthesized by the addition of adenine to CuX$_2$ (X = Cl or Br) by solvent diffusion. Previous experimental studies revealed that both MPMs are selective for C$_2$H$_2$ over CO$_2$ [Xie DY, et al. (2017) ${CIESC J}$ 68: 154--162]. Simulations in MPM-1-Cl and MPM-1-Br were carried out using polarizable and nonpolarizable potentials of the respective sorbates; this was done to investigate the role of explicit induction on the gas sorption mechanism in these materials. The calculated sorption isotherms and isosteric heat of adsorption ($Q_{st}$) valuesfor both sorbates are in reasonable agreement with the corresponding experimental measurements, with simulations using the polarizable models producing the closest overall agreement. The modeled CO$_2$ binding sitein both MPMs was discovered as sorption between the halide ions of two adjacent [Cu$_2$(adenine)$_4$X$_2$]$^{2+}$ (X = Cl, Br) units.In the case of C$_2$H$_2$, it was found that the sorbate molecule prefers to align along the X--Cu--Cu--X axis of the copper paddlewheels suchthat each H atom of the C$_2$H$_2$ molecule can interact favorably with the coordinated X$^-$ ions. The simulations revealed that both MPMs exhibit stronger interactions with C$_2$H$_2$ than CO$_2$, which is consistent with experimental findings. The effect of halogen substitution toward CO$_2$ and C$_2$H$_2$ sorption in two isostructural MPMs was also elucidated in our theoretical studies

Correlation Between Altmetric Attention Scores and Citations for Articles Published in High-Impact Factor Ophthalmology Journals From 2018 to 2019

The Altmetric attention score (AAS) provides new information to gauge the impact of a research article not found through typical metrics, such as impact factor or citation counts. To explore the association between AAS and common impact markers among high-impact ophthalmology journals from 2018 to 2019. All articles published in the American Journal of Ophthalmology (AJO), JAMA Ophthalmology (JAMAO), and Ophthalmology (OPH) from January 1, 2018, to December 31, 2019, were collected for this cross-sectional study. Excluded articles were those missing Altmetric data at the time of data collection. The AAS and associated social media impact for each article were collected with the AAS calculator bookmarklet. Spearman rank correlation analyses and analysis of variance tests were conducted to assess differences in various metrics between AJO, JAMAO, and OPH. The study included articles published of all document types (article, conference paper, editorial, erratum, letter, note, retracted, review, and short survey) and access status (open access and not open access). The correlation between citation counts and Altmetric variables including AAS. A total of 2467 articles were published in the study period. There were 351 articles excluded owing to missing Altmetric data. Of the 2116 articles included in the analysis, 1039 (49.1%) were published in 2018, and 1077 (50.9%) were published in 2019; the mean number of citations was 8.8 (95% CI, 7.9-9.6) for AJO, 6.2 (95% CI, 5.3-7.1) for JAMAO, and 15.1 (95% CI, 13.3-17.0) for OPH. The mean AAS was 4.5 (95% CI, 3.3-5.6) for AJO (723 publications), 27.4 (95% CI, 22.1-32.8) for JAMAO (758 publications), and 15.1 (95% CI, 10.9-19.3) for OPH (635 publications). Citation rate was moderately correlated with AAS across the 3 journals (AJO, ρ = 0.39; P < .001; JAMAO, ρ = 0.41; P < .001; OPH, ρ = 0.40; P < .001), as well as minimally or moderately correlated with engagement or mention by Facebook posts (AJO, ρ = 0.38; P < .001; JAMAO, ρ = 0.24; P < .001; OPH, ρ = 0.20; P < .001), news outlet reporting (AJO, ρ = 0.12; P < .001; JAMAO, ρ = 0.38; P < .001; OPH, ρ = 0.19; P < .001), and Twitter posts (AJO, ρ = 0.40; P < .001; JAMAO, ρ = 0.38; P < .001; OPH, ρ = 0.42; P < .001). Results of this cross-sectional study suggest that citation rate has a moderate positive correlation with online and social media sharing of research in ophthalmology literature. Peer-reviewed journals may increase their reach and impact by sharing their literature through social media and online platforms

Functional Impact of Titin (TTN) Mutations in Ocular Surface Squamous Neoplasia

Mutations in the titin (TTN) gene are among the most common genomic aberrations in ocular surface squamous neoplasia (OSSN), the most common cancer of the external eye. Further, TTN mutations are associated with resistance to standard therapy with topical interferon alpha-2b (IFN-α2b). However, it remains unclear how TTN mutations drive OSSN pathogenesis and treatment resistance. TTN encodes the largest protein in the human body and its best understood function is as a myofibril scaffold in striated muscle. However, recent evidence indicates that TTN has additional functions in non-muscle cells and in cancer. Here, we performed a disorder-based bioinformatics analysis which revealed that intrinsically disordered protein regions are abundant in TTN and provide mechanistic insights into its function as a nuclear protein in epithelial cells. Specific mutations found in OSSN are predicted to affect its intrinsically disordered protein regions (IDPRs), promoting chromosomal instability, oncogenesis, and altered response to IFN-α2b treatment