Protein conformation and biomolecular condensates

Vazquez, Diego S.; Toledo, Pamela L.; Gianotti, Alejo R.; Ermácora, Mario R.

doi:10.1016/j.crstbi.2022.09.004

Cited by 17 publications

(22 citation statements)

References 294 publications

(481 reference statements)

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“…It is noteworthy that coacervation of proteins is a spontaneous assembly process in aqueous solution 17 and can also be described as the response to changes in physicochemical solution conditions, 18 which is called one component self-coacervation. 19 Specifically, spider silk materials 20 are semi-crystalline condensates of ordered domains containing spidroin, 21 which is a large polypeptide with a central repetitive domain and one small globular domain at each end.…”

Section: Introductionmentioning

confidence: 99%

Construction of spidroin coacervate microdroplets and regulation of their morphology

Liu¹,

Nie²,

Tao³

et al. 2023

J. Mater. Chem. B

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Section: Introductionmentioning

confidence: 99%

Construction of spidroin coacervate microdroplets and regulation of their morphology

Liu¹,

Nie²,

Tao³

et al. 2023

J. Mater. Chem. B

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“…In fact, almost all the processes of life activity are continuously changing in organisms, and the inquisition of these physiological and pathological phenomena from a dynamic scale can unveil their intrinsic rules. , Meanwhile, the general opinions believe that biomolecular functions depend mainly on its conformations, or that conformational changes determine its biological functions . Moreover, biomacromolecular conformations are not completely rigid in the body; instead it usually has a high degree of inherent flexibility, which has been proved by some experimental techniques such as nuclear magnetic resonance, computational chemistry, and X-ray diffraction crystallography. , However, the physiological significance of biomolecular conformational flexibility has not yet been fully clarified.…”

Section: Resultsmentioning

confidence: 99%

Dissecting the Enantioselective Neurotoxicity of Isocarbophos: Chiral Insight from Cellular, Molecular, and Computational Investigations

Wang

Peng

et al. 2023

Chem. Res. Toxicol.

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Chiral organophosphorus pollutants are found abundantly in the environment, but the neurotoxicity risks of these asymmetric chemicals to human health have not been fully assessed. Using cellular, molecular, and computational toxicology methods, this story is to explore the static and dynamic toxic actions and its stereoselective differences of chiral isocarbophos toward SH-SY5Y nerve cells mediated by acetylcholinesterase (AChE) and further dissect the microscopic basis of enantioselective neurotoxicity. Cell-based assays indicate that chiral isocarbophos exhibits strong enantioselectivity in the inhibition of the survival rates of SH-SY5Y cells and the intracellular AChE activity, and the cytotoxicity of (S)-isocarbophos is significantly greater than that of (R)-isocarbophos. The inhibitory effects of isocarbophos enantiomers on the intracellular AChE activity are dose-dependent, and the half-maximal inhibitory concentrations (IC50) of (R)-/(S)-isocarbophos are 6.179/1.753 μM, respectively. Molecular experiments explain the results of cellular assays, namely, the stereoselective toxic actions of isocarbophos enantiomers on SH-SY5Y cells are stemmed from the differences in bioaffinities between isocarbophos enantiomers and neuronal AChE. In the meantime, the modes of neurotoxic actions display that the key amino acid residues formed strong noncovalent interactions are obviously different, which are related closely to the molecular structural rigidity of chiral isocarbophos and the conformational dynamics and flexibility of the substrate binding domain in neuronal AChE. Still, we observed that the stable “sandwich-type π–π stacking” fashioned between isocarbophos enantiomers and aromatic Trp-86 and Tyr-337 residues is crucial, which notably reduces the van der Waals’ contribution (ΔG vdW) in the AChE–(S)-isocarbophos complexes and induces the disparities in free energies during the enantioselective neurotoxic conjugations and thus elucidating that (S)-isocarbophos mediated by synaptic AChE has a strong toxic effect on SH-SY5Y neuronal cells. Clearly, this effort can provide experimental insights for evaluating the neurotoxicity risks of human exposure to chiral organophosphates from macroscopic to microscopic levels.

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“…DTT, dithiothreitol; TRX, thioredoxin. (Vazquez et al, 2022). Nanocondensates are deemed important precursors in nucleation processes, such as aggregation, liquid-liquid phase separation, fibrillation, and crystallization, that characterize many physiological and pathological conditions (Choi et al, 2020;Wühr et al, 2022).…”

Section: The Co-condensation Of Resp18hd124 With Insulin or Proinsuli...mentioning

confidence: 99%

“…Conformational disorder is a strong determinant of protein condensation, and most protein engaging in it contain intrinsically disordered domains (IDDs) (Vazquez et al, 2022). The NMR proinsulin structure and the AlphaFold model of RESP18HD exhibit regions that F I G U R E 7 DLS analysis of insulin and co-incubates of RESP18HD124 and insulin.…”

Section: Sequence Conformation and Condensation Propensitymentioning

confidence: 99%

Condensation of the β‐cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain

et al. 2023

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ICA512/PTPRN is a receptor tyrosine‐like phosphatase implicated in the biogenesis and turnover of the insulin secretory granules (SGs) in pancreatic islet beta cells. Previously we found biophysical evidence that its luminal RESP18 homology domain (RESP18HD) forms a biomolecular condensate and interacts with insulin in vitro at close‐to‐neutral pH, that is, in conditions resembling those present in the early secretory pathway. Here we provide further evidence for the relevance of these findings by showing that at pH 6.8 RESP18HD interacts also with proinsulin—the physiological insulin precursor found in the early secretory pathway and the major luminal cargo of β‐cell nascent SGs. Our light scattering analyses indicate that RESP18HD and proinsulin, but also insulin, populate nanocondensates ranging in size from 15 to 300 nm and 10e2 to 10e6 molecules. Co‐condensation of RESP18HD with proinsulin/insulin transforms the initial nanocondensates into microcondensates (size >1 μm). The intrinsic tendency of proinsulin to self‐condensate implies that, in the ER, a chaperoning mechanism must arrest its spontaneous intermolecular condensation to allow for proper intramolecular folding. These data further suggest that proinsulin is an early driver of insulin SG biogenesis, in a process in which its co‐condensation with RESP18HD participates in their phase separation from other secretory proteins in transit through the same compartments but destined to other routes. Through the cytosolic tail of ICA512, proinsulin co‐condensation with RESP18HD may further orchestrate the recruitment of cytosolic factors involved in membrane budding and fission of transport vesicles and nascent SGs.

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Protein conformation and biomolecular condensates

Cited by 17 publications

References 294 publications

Construction of spidroin coacervate microdroplets and regulation of their morphology

Construction of spidroin coacervate microdroplets and regulation of their morphology

Dissecting the Enantioselective Neurotoxicity of Isocarbophos: Chiral Insight from Cellular, Molecular, and Computational Investigations

Condensation of the β‐cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain

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