Tight regulation of unstructured proteins: from transcript synthesis to protein degradation

Abstract

Altered abundance of several intrinsically unstructured proteins (IUPs) has been associated with perturbed cellular signaling that may lead to pathological conditions such as cancer. Therefore, it is important to understand how cells precisely regulate the availability of IUPs. We observed that regulation of transcript clearance, proteolytic degradation, and translational rate contribute to controlling the abundance of IUPs, some of which are present in low amounts and for short periods of time. Abundant phosphorylation and low stochasticity in transcription and translation indicate that the availability of IUPs can be finely tuned. Fidelity in signaling may require that most IUPs be available in appropriate amounts and not present longer than needed.

Fig. 1

The S. cerevisiae proteome was grouped into three categories, the highly structured (S), moderately unstructured (M) and the highly unstructured (U) category based on the fraction of unstructured residues over the entire protein length.

Fig. 2

Box-plots for various regulatory and cellular properties for the three different groups of proteins (S, M and U) in S. cerevisiae. Each box-plot identifies the middle 50% of the data, the median, and the extreme points. The entire set of datapoints is divided into quartiles and the interquartile range (IQR) is calculated as the difference between x_0.75 and x_0.25. The range of the 25% of the data points above (x_0.75) and below (x_0.25) the median (x_0.50) is displayed as a filled box. The horizontal line and the notch represent the median and confidence intervals, respectively. Datapoints greater or less than 1.5*IQR represent outliers and are shown as dots. The horizontal line that is connected by dashed lines above and below the filled box (whiskers) represents the largest and the smallest non-outlier datapoints, respectively. (A) transcriptional complexity, (B) mRNA abundance, (C) mRNA half-life, (D) poly-A tail length (percentage of transcripts that have short poly-A tail length within a group), (E) ribosomal density, (F) protein abundance, (G) protein half-life, (H) PEST-sequence content (percentage of proteins with PEST motif within a group), (I) TATA box content (percentage of genes with a TATA box within a group) and (J) noise (distance from median co-efficient of variation) in protein production. ⁺ denotes statistically significant differences between the S and U group (table S3).

Fig. 3

Box-plots for various regulatory and cellular parameters for the three groups of proteins (S, M and U) in S. pombe (A-D) and humans (E-G). All reported differences are statistically significant (table S4).