Pathological Unfoldomics of Uncontrolled Chaos: Intrinsically Disordered Proteins and Human Diseases

Uversky, Vladimir N.; Davé, Vrushank; Iakoucheva, Lilia M.; Malaney, Prerna; Metallo, Steven J.; Pathak, Rashmi; Joerger, A.C.

doi:10.1021/cr400713r

Cited by 237 publications

(190 citation statements)

References 377 publications

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“…A high percentage (~40%) of all human proteins are partially or completely disordered [4], and many intrinsically disordered proteins (IDP) play important roles in disease mechanisms [5,6], including p53 regulation in cancer pathways, amyloid beta (Aβ) and tau protein aggregation in Alzheimer's disease, α-synuclein in Parkinson's disease, and~80% of cancer-associated and 65% of cell-signaling proteins [7]. It is thought that structural flexibility and plasticity (disorder) provide functional advantage [2,3], which enhances a wide range of physiological pathways involving a disorder-to-order structural transition [8].…”

Section: Introductionmentioning

confidence: 99%

How Closely Related Are Conformations of Protein Ions Sampled by IM-MS to Native Solution Structures?

Chen

Russell

2015

J. Am. Soc. Mass Spectrom.

143

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by "native-state" ESI show a strong dependence on E int . Collisional activation is used to increase E int prior to the ions entering and within the traveling wave (TW) ion mobility analyzer. Comparisons of experimental CCSs with those generated by molecular dynamics (MD) simulation for solution-phase ions and solvent-free ions as a function of temperature provide new insights about conformational preferences and retention of solution conformations. The E int -dependent CCSs, which reveal increased conformational diversity of the ion population, are discussed in terms of folding/unfolding of solvent-free ions. For example, ubiquitin ions that have low internal energies retain native-like conformations, whereas ions that are heated by collisional activation possess higher internal energies and yield a broader range of CCS owing to increased conformational diversity due to losses of secondary and tertiary structures. In contrast, the CCS profile for the IDP apoMT is consistent with kinetic trapping of an ion population composed of a wide range of conformers, and as the E int is increased, these structurally labile conformers unfold to an elongated conformation.

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Section: Introductionmentioning

confidence: 99%

How Closely Related Are Conformations of Protein Ions Sampled by IM-MS to Native Solution Structures?

Chen

Russell

2015

J. Am. Soc. Mass Spectrom.

143

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“…[55][56][57] Furthermore, being general regulators and controllers, many IDPs are intimately associated with the variety of human diseases. 59,60 Since earlier study revealed that proteins related to CVD are enriched in intrinsic disorder, 61 and since T2DM is an important CVD risk factor, we analyzed the intrinsic disorder propensity and the presence of disorderbased functional sites in the biomarkers utilized in this study (human adiponectin, iCAM-1, vCAM-1, and E-selectin) by a series of bioinformatics tools.…”

mentioning

confidence: 99%

Intrinsic disorder in biomarkers of insulin resistance, hypoadiponectinemia, and endothelial dysfunction among the type 2 diabetic patients

Al-Jiffri

Al-Sharif

Al-Jiffri

et al. 2016

Intrinsically Disordered Proteins

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Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that is strongly associated with various complications including cardiovascular diseases and related mortality. The present study aimed to analyze the abundance and functionality of intrinsically disordered regions in several biomarkers of insulin resistance, adiponectin, and endothelial dysfunction found in the T2DM patients. In fact, in comparison to controls, obese T2DM patients are known to have significantly higher levels of inter-cellular adhesion molecule (iCAM-1), vascular cell adhesion molecule (vCAM-1), and E-selectin, whereas their adiponectin levels are relatively low. Bioinformatics analysis revealed that these selected biomarkers (iCAM-1, vCAM-1, E-selectin, and adiponectin) are characterized by the noticeable levels of intrinsic disorder propensity and high binding promiscuity, which are important features expected for proteins serving as biomarkers. Within the limit of studied groups, there is an association between insulin resistance and both hypoadiponectinemia and endothelial dysfunction.

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“…Regarding the latter, it has been recently shown that aggregation of proteins such as Tau, α-synuclein and p53, also termed as intrinsically disordered proteins (IDPs), is able to trigger a cytotoxic response associated with proteasome inhibition. IDPs may also promote aberrant interactions with other proteins, leading to diversion from their functional sites and sequestration into aggregates, thereby enhancing their cytotoxic potential [64,65]. In this context, aggregating intrabodies such as 353-anti-HP1β, anti-CD, anti-Ras and anti-E6 viral protein [8,11,66] could act as IDPs, inducing cell death through co-aggregation and accumulation of crucial proteins and consequent engulfment of the ubiquitin-proteasomal system.…”

Section: Discussionmentioning

confidence: 99%

Intrabody-mediated diverting of HP1β to the cytoplasm induces co-aggregation of H3–H4 histones and lamin-B receptor

Cardinale

Filesi

Singh

et al. 2015

Experimental Cell Research

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HighlightsIntrabodies against heterochromatin protein 1 β (HP1β) inhibit its traffic to the nucleus. Anti-HP1β intrabodies sequester HP1β in cytoplasmic aggregates. Anti-HP1β scFv causes co-aggregation of LBR and H3-H4 histones in the cytoplasm. Methylated histone H3 at K9 (Me9H3) is not affected by anti-HP1β scFv expression. Anti-HP1β scFv induces altered nuclear morphology and apoptosis. Diverting a Q2 protein from its intracellular location is a unique property of intrabodies. To interfere with the intracellular traffic of heterochromatin protein 1β (HP1β) in living cells, we have generated a cytoplasmic targeted anti-HP1β intrabody, specifically directed against the C-terminal portion of the molecule. HP1β is a conserved component of mouse and human constitutive heterochromatin involved in diverse nuclear functions including gene silencing, DNA repair and nuclear membrane assembly. We found that the anti-HP1β intrabody sequesters HP1β into cytoplasmic aggregates, inhibiting its traffic to the nucleus. Lamin B receptor (LBR) and a subset of core histones (H3/H4) are also specifically co-sequestered in the cytoplasm of anti-HP1β intrabody-expressing cells. Methylated histone H3 at K9 (Me9H3), a marker of constitutive heterochromatin, is not affected by the anti-HP1β intrabody expression. Hyper-acetylating conditions completely dislodge H3 from HP1β:LBR containing aggregates. The expression of anti-HP1β scFv fragments induces apoptosis, associated with an alteration of nuclear morphology. Both these phenotypes are specifically rescued either by overexpression of recombinant full length HP1β or by HP1β mutant containing the chromoshadow domain, but not by recombinant LBR protein. The HP1β-chromodomain mutant, on the other hand, does not rescue the phenotypes, but does compete with LBR for binding to HP1β. These findings provide new insights into the mode of action of cytoplasmic-targeted intrabodies and the interaction between HP1β and its binding partners involved in peripheral heterochromatin organisation.

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Pathological Unfoldomics of Uncontrolled Chaos: Intrinsically Disordered Proteins and Human Diseases

Cited by 237 publications

References 377 publications

How Closely Related Are Conformations of Protein Ions Sampled by IM-MS to Native Solution Structures?

How Closely Related Are Conformations of Protein Ions Sampled by IM-MS to Native Solution Structures?

Intrinsic disorder in biomarkers of insulin resistance, hypoadiponectinemia, and endothelial dysfunction among the type 2 diabetic patients

Intrabody-mediated diverting of HP1β to the cytoplasm induces co-aggregation of H3–H4 histones and lamin-B receptor

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