Sequence-based analysis of protein degradation rates

Marrero, Miguel; Dijk, Aalt D. J. van; Ridder, Dick de

doi:10.1002/prot.25323

Cited by 14 publications

(23 citation statements)

References 51 publications

(69 reference statements)

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“…In our models the degrons, including the N-degrons, were features of negligible importance for the prediction of protein lifetimes. This is in line with a recent study that also found little support for the N-end rule in a computational analysis of protein degradation rates in cell cultures 35 . This does not argue against the importance of degrons, or against the N-end rule.…”

Section: Discussionsupporting

confidence: 91%

The codon sequences predict protein lifetimes and other parameters of the protein life cycle in the mouse brain

Mandad

Rahman

Centeno

et al. 2018

Sci Rep

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The homeostasis of the proteome depends on the tight regulation of the mRNA and protein abundances, of the translation rates, and of the protein lifetimes. Results from several studies on prokaryotes or eukaryotic cell cultures have suggested that protein homeostasis is connected to, and perhaps regulated by, the protein and the codon sequences. However, this has been little investigated for mammals in vivo. Moreover, the link between the coding sequences and one critical parameter, the protein lifetime, has remained largely unexplored, both in vivo and in vitro. We tested this in the mouse brain, and found that the percentages of amino acids and codons in the sequences could predict all of the homeostasis parameters with a precision approaching experimental measurements. A key predictive element was the wobble nucleotide. G-/C-ending codons correlated with higher protein lifetimes, protein abundances, mRNA abundances and translation rates than A-/U-ending codons. Modifying the proportions of G-/C-ending codons could tune these parameters in cell cultures, in a proof-of-principle experiment. We suggest that the coding sequences are strongly linked to protein homeostasis in vivo, albeit it still remains to be determined whether this relation is causal in nature.

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Section: Discussionsupporting

confidence: 91%

The codon sequences predict protein lifetimes and other parameters of the protein life cycle in the mouse brain

Mandad

Rahman

Centeno

et al. 2018

Sci Rep

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“…This is particularly important since, analogous to our Sup35 reporter assay, isolated protein fragments are commonly used to initially define regulatory principles, which are then subsequently applied to full-length proteins in their native contexts. Indeed, our data are consistent with numerous previous studies indicating that relationships between protein sequence and degradation rates are rarely absolute on a proteome-wide scale, and degradation rate for a given protein likely results from the culmination and integration of multiple regulatory signals [55][56][57][58][59][60]. Therefore, other factors such as protein localization, proteinprotein interaction, or neighboring protein sequences could influence the proteostatic regulation of proteins containing G-rich and Q/N-rich LCDs.…”

Section: Discussionsupporting

confidence: 91%

Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains

Cascarina

Kaplan

Elder

et al. 2021

IJMS

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Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network is the prevention or reversal of protein aggregation. How proteins aggregate in spite of the anti-aggregation activity of the proteostasis machinery is incompletely understood. Exposed hydrophobic patches can trigger degradation by the ubiquitin-proteasome system, a key branch of the proteostasis network. However, in a recent study, we found that model glycine (G)-rich or glutamine/asparagine (Q/N)-rich prion-like domains differ in their susceptibility to detection and degradation by this system. Here, we expand upon this work by examining whether the features controlling the degradation of our model prion-like domains generalize broadly to G-rich and Q/N-rich domains. Experimentally, native yeast G-rich domains in isolation are sensitive to the degradation-promoting effects of hydrophobic residues, whereas native Q/N-rich domains completely resist these effects and tend to aggregate instead. Bioinformatic analyses indicate that native G-rich domains from yeast and humans tend to avoid degradation-promoting features, suggesting that the proteostasis network may act as a form of selection at the molecular level that constrains the sequence space accessible to G-rich domains. However, the sensitivity or resistance of G-rich and Q/N-rich domains, respectively, was not always preserved in their native protein contexts, highlighting that proteins can evolve other sequence features to overcome the intrinsic sensitivity of some LCDs to degradation.

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“…The CTD is rich in proline (11%) and arginine (9%) residues and most probably intrinsically disordered. Sequence comparison revealed a prion-like domain (PrlD) 26 and putative PEST sequences 27 , which most probably relate to lower stability of the protein because of their intrinsic disorder 28 .…”

Section: Resultsmentioning

confidence: 99%

JASPer controls interphase histone H3S10 phosphorylation by chromosomal kinase JIL-1 in Drosophila

et al. 2019

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In flies, the chromosomal kinase JIL-1 is responsible for most interphase histone H3S10 phosphorylation and has been proposed to protect active chromatin from acquiring heterochromatic marks, such as dimethylated histone H3K9 (H3K9me2) and HP1. Here, we show that JIL-1’s targeting to chromatin depends on a PWWP domain-containing protein JASPer (JIL-1 Anchoring and Stabilizing Protein). JASPer-JIL-1 (JJ)-complex is the major form of kinase in vivo and is targeted to active genes and telomeric transposons via binding of the PWWP domain of JASPer to H3K36me3 nucleosomes, to modulate transcriptional output. JIL-1 and JJ-complex depletion in cycling cells lead to small changes in H3K9me2 distribution at active genes and telomeric transposons. Finally, we identify interactors of the endogenous JJ-complex and propose that JIL-1 not only prevents heterochromatin formation but also coordinates chromatin-based regulation in the transcribed part of the genome.

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Sequence-based analysis of protein degradation rates

Cited by 14 publications

References 51 publications

The codon sequences predict protein lifetimes and other parameters of the protein life cycle in the mouse brain

The codon sequences predict protein lifetimes and other parameters of the protein life cycle in the mouse brain

Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains

JASPer controls interphase histone H3S10 phosphorylation by chromosomal kinase JIL-1 in Drosophila

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