Genetic variation associated with condensate dysregulation in disease

Banani, Salman F.; Afeyan, Lena K.; Hawken, Susana Wilson; Henninger, Jonathan E.; Dall’Agnese, Alessandra; Clark, Victoria; Platt, Jesse M.; Oksuz, Ozgur; Hannett, Nancy M.; Sagi, Ido; Lee, Tong Ihn; Young, Richard A.

doi:10.1016/j.devcel.2022.06.010

Cited by 48 publications

(33 citation statements)

References 147 publications

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“…Moreover, condensates of some IDPs reconstituted in vitro tend to undergo a transition to a dynamically-arrested state, wherein oligomeric species can nucleate and ultimately aggregate into fibrils [6,7,2,3,8,9,10,11,12,13,14]. As accumulating evidence suggests that these processes may be involved in neurodegeneration and cancer [15,16,17,18], understanding how PS and rheological properties of condensates depend on protein sequence is a current research focus.…”

Section: Introductionmentioning

confidence: 99%

Improved Predictions of Phase Behaviour of Intrinsically Disordered Proteins by Tuning the Interaction Range

Tesei

Lindorff‐Larsen

2022

Preprint

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The formation and viscoelastic properties of condensates of intrinsically disordered proteins (IDPs) is dictated by amino acid sequence and solution conditions. Because of the involvement of biomolecular condensates in cell physiology and disease, furthering our understanding of the relationship between protein sequence and phase separation (PS) may have important implications in formulating new therapeutic hypotheses. Here, we present CALVADOS 2, a coarse-grained model of IDPs that accurately predicts conformational properties and propensity to undergo PS for diverse sequences and solution conditions. In particular, we systematically study the effect of varying the range of nonionic interactions and use our findings to improve the temperature scale of the model. We further optimize the residue-specific model parameters against experimental data on the chain compaction of 55 proteins and 70 hydrophobicity scales from the literature. Extensive testing shows that the model accurately predicts chain compaction and PS propensity for sequences of diverse length, charge patterning, and at disparate temperatures and salt concentrations.

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Section: Introductionmentioning

confidence: 99%

Improved Predictions of Phase Behaviour of Intrinsically Disordered Proteins by Tuning the Interaction Range

Tesei

Lindorff‐Larsen

2022

Preprint

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“…As a counterpart to the wide range of the cellular processes described above, it is becoming increasingly clear that failures in the regulation of condensed states may lead to dysfunctional protein assemblies that could be involved in a range of pathological processes 22,35,36 .…”

Section: Protein Condensation Diseasesmentioning

confidence: 99%

Protein condensation diseases: therapeutic opportunities

Vendruscolo

Fuxreiter

2022

Nat Commun

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Condensed states of proteins, including liquid-like membraneless organelles and solid-like aggregates, contribute in fundamental ways to the organisation and function of the cell. Perturbations of these states can lead to a variety of diseases through mechanisms that we are now beginning to understand. We define protein condensation diseases as conditions caused by the disruption of the normal behaviour of the condensed states of proteins. We analyze the problem of the identification of targets for pharmacological interventions for these diseases and explore opportunities for the regulation of the formation and organisation of aberrant condensed states of proteins.

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“…Pathogenic nonsynonmous substitution mutations were obtained from a prior dataset of pathogenic mutations that integrated multiple databases of somatic and germline variation associated with cancer and Mendelian disorders, including ClinVar (accessed January 29, 2021) and HGMD v2020.4 in hg38. Cancer variants were obtained from AACR Project GENIE v8.1 (AACR Project GENIE Consortium, 2017) and various TCGA and TARGET studies via cBioPortal (accessed January, 2021) (Banani et al, 2022). Mutations were subsetted for those affecting TF-ARMs.…”

Section: Overlap Of Pathogenic Mutations In Tf-armsmentioning

confidence: 99%

Transcription factors interact with RNA to regulate genes

Oksuz

Henninger

Warneford-Thomson

et al. 2022

Preprint

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Transcription factors (TFs) orchestrate the gene expression programs that define each cell's identity. The canonical TF accomplishes this with two domains, one that binds specific DNA sequences and the other that binds protein coactivators or corepressors. We find that at least half of TFs also bind RNA, doing so through a previously unrecognized domain with sequence and functional features analogous to the arginine-rich motif of the HIV transcriptional activator Tat. RNA-binding contributes to TF function by promoting the dynamic association between DNA, RNA and TF on chromatin. TF-RNA interactions are a conserved feature essential for vertebrate development and disrupted in disease. We propose that the ability to bind DNA, RNA and protein is a general property of many TFs and is fundamental to their gene regulatory function.

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Genetic variation associated with condensate dysregulation in disease

Cited by 48 publications

References 147 publications

Improved Predictions of Phase Behaviour of Intrinsically Disordered Proteins by Tuning the Interaction Range

Improved Predictions of Phase Behaviour of Intrinsically Disordered Proteins by Tuning the Interaction Range

Protein condensation diseases: therapeutic opportunities

Transcription factors interact with RNA to regulate genes

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