IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding

Mészáros, Bálint; Erdős, Gábor; Dosztányi, Zsuzsanna

doi:10.1093/nar/gky384

Cited by 1,208 publications

(1,212 citation statements)

References 54 publications

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“…39,42,50,51 PrP possesses most of the physicochemical characteristics necessary to drive LLPS (Figure 6), including significant levels of intrinsic disorder and capability to interact with NAs. 56,57 Furthermore, at least 35.9% of the PrP 90-231 residues are predicted to be disordered. Representative DIC micrographs of rPrP 90-231 :aptamers after 10 minutes incubation at 1:1, 2:1 and 5:1 molar ratios, respectively, in 10 mM Tris (pH 7.4), 100 mM NaCl in presence of A1 (A), A2 (B) or A1_mut (C).…”

Section: Discussionmentioning

confidence: 99%

Liquid‐liquid phase separation and fibrillation of the prion protein modulated by a high‐affinity DNA aptamer

et al. 2019

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Structural conversion of cellular prion protein (PrP C ) into scrapie PrP (PrP Sc ) and subsequent aggregation are key events associated with the onset of transmissible spongiform encephalopathies (TSEs). Experimental evidence supports the role of nucleic acids (NAs) in assisting this conversion. Here, we asked whether PrP undergoes liquid-liquid phase separation (LLPS) and if this process is modulated by NAs. To this end, two 25-mer DNA aptamers, A1 and A2, were selected against the globular domain of recombinant murine PrP (rPrP 90-231 ) using SELEX methodology. Multiparametric structural analysis of these aptamers revealed that A1 adopts a hairpin conformation. Aptamer binding caused partial unfolding of rPrP 90-231 and modulated its ability to undergo LLPS and fibrillate. In fact, although free rPrP phase separated into large droplets, aptamer binding increased the number of droplets but noticeably reduced their size. Strikingly, a modified A1 aptamer that does not adopt a hairpin structure induced formation of amyloid fibrils on the surface of the droplets. We show here that PrP undergoes LLPS, and that the PrP interaction with NAs modulates phase separation and promotes PrP fibrillation in a NA structure and concentration-dependent manner. These results shed new light on the roles of NAs in PrP misfolding and TSEs. |

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Section: Discussionmentioning

confidence: 99%

Liquid‐liquid phase separation and fibrillation of the prion protein modulated by a high‐affinity DNA aptamer

et al. 2019

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“…The sequence features of MoRFs are distinct from the rest portion of IDPs/IDRs, enabling development of predictors to identify MoRFs . For example, ANCHOR predicts disordered binding regions based on the pairwise energy estimation from IUPred . Usually, upon binding to their partners, MoRFs undergo disorder‐to‐order transitions.…”

Section: Molecular Recognition Featuresmentioning

confidence: 99%

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

et al. 2019

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The sequence–structure–function paradigm of proteins has been revolutionized by the discovery of intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). In contrast to traditional ordered proteins, IDPs/IDRs are unstructured under physiological conditions. The absence of well‐defined three‐dimensional structures in the free state of IDPs/IDRs is fundamental to their function. Folding upon binding is an important mode of molecular recognition for IDPs/IDRs. While great efforts have been devoted to investigating the complex structures and binding kinetics and affinities, our knowledge on the binding mechanisms of IDPs/IDRs remains very limited. Here, we review recent advances on the binding mechanisms of IDPs/IDRs. The structures and kinetic parameters of IDPs/IDRs can vary greatly, and the binding mechanisms can be highly dependent on the structural properties of IDPs/IDRs. IDPs/IDRs can employ various combinations of conformational selection and induced fit in a binding process, which can be templated by the target and/or encoded by the IDP/IDR. Further studies should provide deeper insights into the molecular recognition of IDPs/IDRs and enable the rational design of IDP/IDR binding mechanisms in the future.

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“…The~600 aa middle part of UTX, highlighted in red, is most likely highly disordered according to the IUPred2 prediction tool 15. (a) Structure of the UTX protein with the two defined domains, TPR (orange) and JmjC (green/blue) indicated.…”

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confidence: 99%

The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

Schulz

Lang

Koch

et al. 2019

Intl Journal of Cancer

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The lysine‐specific demethylase 6A/UTX (gene name KDM6A) acts as a component of the COMPASS complex to control gene activation. UTX demethylates H3K27me2/3 at genes and enhancers. Deleterious mutations in KDM6A are found in many cancer types, prominently urothelial carcinoma and certain T‐cell leukemias. In certain cancers, however, UTX supports oncogenic transcription factors, e.g. steroid hormone receptors in breast and prostate cancer. In fetal development, UTX regulates lineage choice and cell differentiation. Analogously, loss of UTX function in cancer may lead to metaplasia or impede differentiation. Likely because its function is contingent on its interacting transcription factors, the effects of UTX inactivation are not uniform and require detailed investigation in each cancer type. In urothelial carcinoma, in particular, the functional consequences of the frequent mutations in KDM6A and other COMPASS component genes are poorly understood. Nevertheless, UTX inactivation appears to sensitize many cancers to inhibitors of the H3K27 methyltransferase EZH2. Conversely, inhibitors of UTX enzymatic activity may be applicable in cancers with an oncogenic UTX function. Intriguingly, the fact that KDM6A is localized on the X‐chromosome, but both copies are expressed, may account for gender‐specific differences in cancer susceptibility. In conclusion, despite recent progress, many open questions need to be addressed, most importantly, the detailed mechanisms by which KDM6A inactivation promotes various cancers, but also with which proteins UTX interacts in and apart from the COMPASS complex, and to which extent its catalytic function is required for its tumor‐suppressive function.

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IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding

Cited by 1,208 publications

References 54 publications

Liquid‐liquid phase separation and fibrillation of the prion protein modulated by a high‐affinity DNA aptamer

Liquid‐liquid phase separation and fibrillation of the prion protein modulated by a high‐affinity DNA aptamer

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

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