Spatial positions of homopolymeric repeats in the human proteome and their effect on cellular toxicity

Siwach, Pratibha; Sengupta, Suman; Parihar, Rashmi; Ganesh, Subramaniam

doi:10.1016/j.bbrc.2009.01.101

Cited by 8 publications

(8 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Signal peptides are cleaved off early in the course of translation and then degraded rapidly [36]. This could explain why leucine repeats, which in general are toxic [28–30,32], are tolerated at such high frequencies. Further analysis confirmed a selective enrichment of leucine repeats in signal peptides that could not be explained by differences in the amino acid composition of these segments and the mature proteins.…”

Section: Discussionmentioning

confidence: 99%

“…This is surprising because the cytotoxicity of amino acids repeats is highly correlated with their hydrophobicity and their length [28][29][30]. The observed toxicity may result from an aggregation of such repeats [29,31,32].…”

Section: Discussionmentioning

confidence: 99%

“…Signal peptides are cleaved off early in the course of translation and then degraded rapidly [36]. This could explain why leucine repeats, which in general are toxic [28][29][30]32], are tolerated at such high frequencies.…”

Section: Localization Of Saars In Signal Peptidesmentioning

confidence: 99%

See 2 more Smart Citations

Single amino acid repeats in signal peptides

Łabaj¹,

Leparc²,

Bardet³

et al. 2010

The FEBS Journal

View full text Add to dashboard Cite

There has been an increasing interest in single amino acid repeats ever since it was shown that these are the cause of a variety of diseases. Although a systematic study of single amino acid repeats is challenging, they have subsequently been implicated in a number of functional roles. In general surveys, leucine runs were among the most frequent. In the present study, we present a detailed investigation of repeats in signal peptides of secreted and type I membrane proteins in comparison with their mature parts. We focus on eukaryotic species because single amino acid repeats are generally rather rare in archaea and bacteria. Our analysis of over 100 species shows that repeats of leucine (but not of other hydrophobic amino acids) are over‐represented in signal peptides. This trend is most pronounced in higher eukaryotes, particularly in mammals. In the human proteome, although less than one‐fifth of all proteins have a signal peptide, approximately two‐thirds of all leucine repeats are located in these transient regions. Signal peptides are cleaved early from the growing polypeptide chain and then degraded rapidly. This may explain why leucine repeats, which can be toxic, are tolerated at such high frequencies. The substantial fraction of proteins affected by the strong enrichment of repeats in these transient segments highlights the bias that they can introduce for systematic analyses of protein sequences. In contrast to a general lack of conservation of single amino acid repeats, leucine repeats were found to be more conserved than the remaining signal peptide regions, indicating that they may have an as yet unknown functional role.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Single amino acid repeats in signal peptides

Łabaj¹,

Leparc²,

Bardet³

et al. 2010

The FEBS Journal

View full text Add to dashboard Cite

show abstract

“…The amino-end of the growing polypeptide chain of secreted and many membrane proteins contains a signal peptide, with a central part rich in hydrophobic amino acids. It has been observed that the location of many SAARs shows a positional bias towards the termini of polypeptides [34,38-40]. Although a possible association of leucine repeats with signal peptides has been suggested earlier [34], there has been no systematic study of repeat enrichment in signal peptides.…”

Section: Resultsmentioning

confidence: 99%

An analysis of single amino acid repeats as use case for application specific background models

2011

View full text Add to dashboard Cite

BackgroundSequence analysis aims to identify biologically relevant signals against a backdrop of functionally meaningless variation. Increasingly, it is recognized that the quality of the background model directly affects the performance of analyses. State-of-the-art approaches rely on classical sequence models that are adapted to the studied dataset. Although performing well in the analysis of globular protein domains, these models break down in regions of stronger compositional bias or low complexity. While these regions are typically filtered, there is increasing anecdotal evidence of functional roles. This motivates an exploration of more complex sequence models and application-specific approaches for the investigation of biased regions.ResultsTraditional Markov-chains and application-specific regression models are compared using the example of predicting runs of single amino acids, a particularly simple class of biased regions. Cross-fold validation experiments reveal that the alternative regression models capture the multi-variate trends well, despite their low dimensionality and in contrast even to higher-order Markov-predictors. We show how the significance of unusual observations can be computed for such empirical models. The power of a dedicated model in the detection of biologically interesting signals is then demonstrated in an analysis identifying the unexpected enrichment of contiguous leucine-repeats in signal-peptides. Considering different reference sets, we show how the question examined actually defines what constitutes the 'background'. Results can thus be highly sensitive to the choice of appropriate model training sets. Conversely, the choice of reference data determines the questions that can be investigated in an analysis.ConclusionsUsing a specific case of studying biased regions as an example, we have demonstrated that the construction of application-specific background models is both necessary and feasible in a challenging sequence analysis situation.

show abstract

“…In addition, expansions of polyalanine repeat in transcription factors result in misfolding, degradation and cytoplasmic aggregation of the mutant proteins (Albrecht et al 2004). In addition, the evolution of repeat tracts in the proteome appears to be selected for or against by the cellular toxicity (Siwach et al 2009). All these results indicate that any change in polyalanine tracts may result in deleterious effects.…”

mentioning

confidence: 98%

Expansion of polyalanine tracts in the QA domain may play a critical role in the clavicular development of cleidocranial dysplasia

Lei

et al. 2015

J Genet

View full text Add to dashboard Cite

Spatial positions of homopolymeric repeats in the human proteome and their effect on cellular toxicity

Cited by 8 publications

References 22 publications

Single amino acid repeats in signal peptides

Single amino acid repeats in signal peptides

An analysis of single amino acid repeats as use case for application specific background models

Expansion of polyalanine tracts in the QA domain may play a critical role in the clavicular development of cleidocranial dysplasia

Contact Info

Product

Resources

About