Aggregation properties of a disordered protein are tunable by pH and depend on its net charge per residue

Tedeschi, Giulia; Mangiagalli, Marco; Chmielewska, Sara; Lotti, Marina; Natalello, Antonino; Brocca, Stefania

doi:10.1016/j.bbagen.2017.09.002

Cited by 30 publications

(32 citation statements)

References 43 publications

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“…Lyophilized proteins were suspended in 25 m m phosphate buffer (pH 7.0) to a concentration of 8 μ m . CD spectra were measured using a J‐815 spectropolarimeter (Jasco Corp., Easton, MD, USA) in 1‐mm path length cuvette as described . In experiments aimed to assess thermal stability spectra were collected by measuring the CD signal at 215 nm fixed wavelength, and the sample was progressively heated from 25 to 90 °C.…”

Section: Methodsmentioning

confidence: 99%

Structure of a bacterial ice binding protein with two faces of interaction with ice

et al. 2018

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Section: Methodsmentioning

confidence: 99%

Structure of a bacterial ice binding protein with two faces of interaction with ice

et al. 2018

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“…The experimental data was obtained from Tedeschi et al [33]. The pH-dependent experimental solubility of a model IDP was used as training set to parameterize a function that describes protein solubility as a function of pH.…”

Section: Solubility Modellingmentioning

confidence: 99%

“…However, it is well known that the partition coefficients of the neutral and charged species of ionizable amino acids, and therefore their hydrophobicity, depend on the pH of the solution [31,32]. Moreover, the electrostatic properties of proteins, i.e., their net charge in a given solution, are also connected to the solution pH, being important determinants of protein solubility [33,34].…”

Section: Introductionmentioning

confidence: 99%

pH-Dependent Aggregation in Intrinsically Disordered Proteins Is Determined by Charge and Lipophilicity

Santos

Iglesias

Santos-Suárez

et al. 2020

Cells

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Protein aggregation is associated with an increasing number of human disorders and premature aging. Moreover, it is a central concern in the manufacturing of recombinant proteins for biotechnological and therapeutic applications. Nevertheless, the unique architecture of protein aggregates is also exploited by nature for functional purposes, from bacteria to humans. The relevance of this process in health and disease has boosted the interest in understanding and controlling aggregation, with the concomitant development of a myriad of algorithms aimed to predict aggregation propensities. However, most of these programs are blind to the protein environment and, in particular, to the influence of the pH. Here, we developed an empirical equation to model the pH-dependent aggregation of intrinsically disordered proteins (IDPs) based on the assumption that both the global protein charge and lipophilicity depend on the solution pH. Upon its parametrization with a model IDP, this simple phenomenological approach showed unprecedented accuracy in predicting the dependence of the aggregation of both pathogenic and functional amyloidogenic IDPs on the pH. The algorithm might be useful for diverse applications, from large-scale analysis of IDPs aggregation properties to the design of novel reversible nanofibrillar materials.

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“…On the other hand, intrinsically disordered proteins lack of a well-defined structure and have a more relaxed conformation because their sequences are depleted in hydrophobic amino acids. The accompanying enrichment in polar and charged amino acids, as a general rule, causes intrinsically disordered proteins to be soluble in aqueous solutions [18,21] and to have higher solvent accessibility than globular proteins [41][42][43]. Coherently, we found that IDPs are characterized by the highest values of solubility and of accessible surface area with respect to the rest of the human proteome ( Fig.…”

Section: Idps Are More Soluble and Have Higher Solvent Accessibility mentioning

confidence: 73%

“…The combination of a relatively low proportion of hydrophobic residues, a relatively high proportion of charged and polar residues, and high solvent accessibility represents an hallmark of IDPs [2,3,17]. All these features were shown to be associated with increased protein solubility [2,3,18], which is an important thermodynamic property in structural and biophysical studies.…”

Section: Introductionmentioning

confidence: 99%

Variants of intrinsic disorder: structural characterization

Forcelloni

Deiana

Giansanti

2019

Preprint

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In a recent study, we have introduced an operational classification of the human proteome in three variants of disorder: ordered proteins (ORDPs), structured proteins with intrinsically disordered protein regions (IDPRs), intrinsically disordered proteins (IDPs). That classification was useful in functionally separating IDPRs from IDPs, which up until now have been generally considered as a whole. In this study, we corroborate this distinction by considering different physical-chemical and structural properties. Both ORDPs and IDPRs are enriched in order-promoting amino acids, whereas only IDPs show an enrichment in disordered-promoting amino acids. Consistently, ORDPs and IDPRs are preferentially located in the ordered phase of the charge-hydropathy plot, whereas IDPs are widespread over the disordered phase. We introduce the mean packing -mean pairwise energy (MP-MPE) plane to structurally characterize these variants even in the absence of a structural model. As expected for well-packed proteins, a negative linear correlation is observed between MP and MPE for ORDPs and IDPRs, whereas IDPs break this linear dependence. Finally, we find that IDPs have a more extended conformation as measured by the scaling law between the radius of gyration and the length of these proteins, and accordingly they have higher solubility and accessible surface area than ORDPs and IDPRs. Overall, our results confirm the relevance of our operational separation of IDPRs from IDPs and provide further validation of our criteria to separate IDPs from the rest of human proteome.

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Aggregation properties of a disordered protein are tunable by pH and depend on its net charge per residue

Cited by 30 publications

References 43 publications

Structure of a bacterial ice binding protein with two faces of interaction with ice

Structure of a bacterial ice binding protein with two faces of interaction with ice

pH-Dependent Aggregation in Intrinsically Disordered Proteins Is Determined by Charge and Lipophilicity

Variants of intrinsic disorder: structural characterization

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