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Features of reactive cysteines discovered through computation: from kinase inhibition to enrichment around protein degrons.

ABSTRACT: Large-scale characterisation of cysteine modification is enabling study of the physicochemical determinants of reactivity. We find that location of cysteine at the amino terminus of an ?-helix, associated with activity in thioredoxins, is under-represented in human protein structures, perhaps indicative of selection against background reactivity. An amino-terminal helix location underpins the covalent linkage for one class of kinase inhibitors. Cysteine targets for S-palmitoylation, S-glutathionylation, and S-nitrosylation show little correlation with pKa values predicted from structures, although flanking sequences of S-palmitoylated sites are enriched in positively-charged amino acids, which could facilitate palmitoyl group transfer to substrate cysteine. A surprisingly large fraction of modified sites, across the three modifications, would be buried in native protein structure. Furthermore, modified cysteines are (on average) closer to lysine ubiquitinations than are unmodified cysteines, indicating that cysteine redox biology could be associated with protein degradation and degron recognition.

SUBMITTER: Fowler NJ

PROVIDER: S-EPMC5703995 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Features of reactive cysteines discovered through computation: from kinase inhibition to enrichment around protein degrons.

Fowler Nicholas J NJ Blanford Christopher F CF de Visser Sam P SP Warwicker Jim J

Scientific reports 20171127 1

Large-scale characterisation of cysteine modification is enabling study of the physicochemical determinants of reactivity. We find that location of cysteine at the amino terminus of an α-helix, associated with activity in thioredoxins, is under-represented in human protein structures, perhaps indicative of selection against background reactivity. An amino-terminal helix location underpins the covalent linkage for one class of kinase inhibitors. Cysteine targets for S-palmitoylation, S-glutathion ...[more]

PMID: 29180682

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Project description:Brain injuries of different etiologies lead to irreversible neuronal loss and persisting neuronal deficits. New therapeutic strategies are emerging to compensate neuronal damage upon brain injury. Some of these strategies focus on enhancing endogenous generation of neurons from neural stem cells (NSCs) to substitute the dying neurons. However, the capacity of the injured brain to produce new neurons is limited, especially in cases of extensive injury. This reduced neurogenesis is a consequence of the effect of signaling molecules released in response to inflammation, which act on intracellular pathways, favoring gliogenesis and preventing recruitment of neuroblasts from neurogenic regions. Protein kinase C (PKC) is a family of intracellular kinases involved in several of these gliogenic signaling pathways. The aim of this study was to analyze the role of PKC isozymes in the generation of neurons from neural progenitor cells (NPCs) in vitro and in vivo in brain injuries. PKC inhibition in vitro, in cultures of NPC isolated from the subventricular zone (SVZ) of postnatal mice, leads differentiation towards a neuronal fate. This effect is not mediated by classical or atypical PKC. On the contrary, this effect is mediated by novel PKCε, which is abundantly expressed in NPC cultures under differentiation conditions. PKCε inhibition by siRNA promotes neuronal differentiation and reduces glial cell differentiation. On the contrary, inhibition of PKCθ exerts a small anti-gliogenic effect and reverts the effect of PKCε inhibition on neuronal differentiation when both siRNAs are used in combination. Interestingly, in cortical brain injuries we have found expression of almost all PKC isozymes found in vitro. Inhibition of PKC activity in this type of injuries leads to neuronal production. In conclusion, these findings show an effect of PKCε in the generation of neurons from NPC in vitro, and they highlight the role of PKC isozymes as targets to produce neurons in brain lesions.

Dataset Information

Features of reactive cysteines discovered through computation: from kinase inhibition to enrichment around protein degrons.

Publications

Features of reactive cysteines discovered through computation: from kinase inhibition to enrichment around protein degrons.

Similar Datasets

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