Portrait of the Intrinsically Disordered Side of the HTLV-1 Proteome

Lyngdoh, Denzelle Lee; Shukla, Harish; Sonkar, Amit; Anupam, Rajaneesh; Tripathi, Timir

doi:10.1021/acsomega.9b01017

Cited by 18 publications

(13 citation statements)

References 99 publications

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“…We also determined the mean PPID values of the top 20 affinity-attenuating designs and found that the values ranged between 0.72% and 1.08% ( Table S1 ). Based on the overall level of intrinsic disorder content, proteins can be classified into three classes: highly ordered (PPID <10%), moderately disordered (PPID between 11% and 30%), and highly disordered (PPID ≥30%) ( Lyngdoh et al., 2019 ; Uversky, 2013 ). All these data indicate negligible changes in the structural content in the affinity-attenuating designs, i.e., mutations did not induce any changes in the structural features of the affinity-attenuating designs.…”

Section: Resultsmentioning

confidence: 99%

High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance

et al. 2021

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The use of remdesivir to treat COVID-19 will likely continue before clinical trials are completed. Due to the lengthening pandemic and evolving nature of the virus, predicting potential residues prone to mutation is crucial for the management of remdesivir resistance. Using a rational ligand-based interface design complemented with mutational mapping, we generated a total of 100,000 mutations and provided insight into the functional outcomes of mutations in the remdesivir-binding site in nsp12 subunit of RdRp. After designing 46 residues in the remdesivir-binding site of nsp12, the designs retained 97%-98% sequence identity, suggesting that very few mutations in nsp12 are required for SARS-CoV-2 to attain remdesivir resistance. Several mutants displayed decreased binding affinity to remdesivir, suggesting drug resistance. These hotspot residues had a higher probability of undergoing selective mutation and thus conferring remdesivir resistance. Identifying the potential residues prone to mutation improves our understanding of SARS-CoV-2 drug resistance and COVID-19 pathogenesis.

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Section: Resultsmentioning

confidence: 99%

High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance

et al. 2021

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“…Intrinsically disordered proteins (IDPs) have been linked to multiple malignancies, and approximately 70% of human cancer-associated proteins have been predicted to retain disordered regions [ 45 , 46 ]. Moreover, intrinsic disorders have been observed in crucial oncoproteins of multiple human oncogenic viruses, including human papillomavirus (HPV) [ 47 , 48 ], human T lymphotropic virus type 1 (HTLV-1) [ 49 ] and Kaposi’s sarcoma-associated herpesvirus (KSHV) [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth

Nwogu

Ortiz

Kwun

2020

Viruses

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Merkel cell polyomavirus (MCV) is the only known human oncogenic virus in the polyomaviridae family and the etiological agent of most Merkel cell carcinomas (MCC). MCC is an aggressive and highly metastatic skin cancer with a propensity for recurrence and poor prognosis. Large tumor antigen (LT), is an essential oncoprotein for MCV transcription, viral replication, and cancer cell proliferation. MCV LT is a short-lived protein that encodes a unique domain: MCV LT unique regions (MURs). These domains consist of phosphorylation sites that interact with multiple E3 ligases, thus limiting LT expression and consequently, viral replication. In this study, we show that MURs are necessary for regulating LT stability via multiple E3 ligase interactions, resulting in cell growth arrest. While expression of wild-type MCV LT induced a decrease in cellular proliferation, deletion of the MUR domains resulted in increased LT stability and cell proliferation. Conversely, addition of MURs to SV40 LT propagated E3 ligase interactions, which in turn, reduced SV40 LT stability and decreased cell growth activity. Our results demonstrate that compared to other human polyomaviruses (HPyVs), MCV LT has evolved to acquire the MUR domains that are essential for MCV LT autoregulation, potentially leading to viral latency and MCC.

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“…A common strategy is to use insertion or substitution sites in the endogenous antigenic regions of the L1 protein to attach the epitope of interest based on information derived from B-cell epitope mapping [ 54 , 55 ]. Additionally, IDRs in viral capsid proteins have been used as targets for vaccine or drug therapies [ 56 , 57 , 58 , 59 ]. Thus, we used VLPs to evaluate the immunogenicity of sDE1 and sDE3.…”

Section: Resultsmentioning

confidence: 99%

Short Disordered Epitope of CRTAM Ig-Like V Domain as a Potential Target for Blocking Antibodies

Vázquez-Martínez

Gómez-Lim

Morales-Ríos

et al. 2020

IJMS

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Class-I Restricted T Cell-Associated Molecule (CRTAM) is a protein that is expressed after T cell activation. The interaction of CRTAM with its ligand, nectin-like 2 (Necl2), is required for the efficient production of IL-17, IL-22, and IFNγ by murine CD4 T cells, and it plays a role in optimal CD8 T and NK cell cytotoxicity. CRTAM promotes the pro-inflammatory cytokine profile; therefore, it may take part in the immunopathology of autoimmune diseases such as diabetes type 1 or colitis. Thus, antibodies that block the interaction between CRTAM and Necl2 would be useful for controlling the production of these inflammatory cytokines. In this work, using bioinformatics predictions, we identified three short disordered epitopes (sDE1-3) that are located in the Ig-like domains of murine CRTAM and are conserved in mammalian species. We performed a structural analysis by molecular dynamics simulations of sDE1 (QHPALKSSKY, Ig-like V), sDE2 (QRNGEKSVVK, Ig-like C1), and sDE3 (CSTERSKKPPPQI, Ig-like C1). sDE1, which is located within a loop of the contact interface of the heterotypic interaction with Nectl2, undergoes an order–disorder transition. On the contrary, even though sDE2 and sDE3 are flexible and also located within loops, they do not undergo order–disorder transitions. We evaluated the immunogenicity of sDE1 and sDE3 through the expression of these epitopes in chimeric L1 virus-like particles. We confirmed that sDE1 induces polyclonal antibodies that recognize the native folding of CRTAM expressed in activated murine CD4 T cells. In contrast, sDE3 induces polyclonal antibodies that recognize the recombinant protein hCRTAM-Fc, but not the native CRTAM. Thus, in this study, an exposed disordered epitope in the Ig-like V domain of CRTAM was identified as a potential site for therapeutic antibodies.

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Portrait of the Intrinsically Disordered Side of the HTLV-1 Proteome

Cited by 18 publications

References 99 publications

High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance

High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance

Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth

Short Disordered Epitope of CRTAM Ig-Like V Domain as a Potential Target for Blocking Antibodies

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