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  1. Abstract Summary

    Low-complexity domains (LCDs) in proteins are regions enriched in a small subset of amino acids. LCDs exist in all domains of life, often have unusual biophysical behavior, and function in both normal and pathological processes. We recently developed an algorithm to identify LCDs based predominantly on amino acid composition thresholds. Here, we have integrated this algorithm with a webserver and augmented it with additional analysis options. Specifically, users can (i) search for LCDs in whole proteomes by setting minimum composition thresholds for individual or grouped amino acids, (ii) submit a known LCD sequence to search for similar LCDs, (iii) search for and plot LCDs within a single protein, (iv) statistically test for enrichment of LCDs within a user-provided protein set and (v) specifically identify proteins with multiple types of LCDs.

    Availability and implementation

    The LCD-Composer server can be accessed at http://lcd-composer.bmb.colostate.edu. The corresponding command-line scripts can be accessed at https://github.com/RossLabCSU/LCD-Composer/tree/master/WebserverScripts.

     
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  2. 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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  3. null (Ed.)
    Abstract Low complexity domains (LCDs) in proteins are regions predominantly composed of a small subset of the possible amino acids. LCDs are involved in a variety of normal and pathological processes across all domains of life. Existing methods define LCDs using information-theoretical complexity thresholds, sequence alignment with repetitive regions, or statistical overrepresentation of amino acids relative to whole-proteome frequencies. While these methods have proven valuable, they are all indirectly quantifying amino acid composition, which is the fundamental and biologically-relevant feature related to protein sequence complexity. Here, we present a new computational tool, LCD-Composer, that directly identifies LCDs based on amino acid composition and linear amino acid dispersion. Using LCD-Composer's default parameters, we identified simple LCDs across all organisms available through UniProt and provide the resulting data in an accessible form as a resource. Furthermore, we describe large-scale differences between organisms from different domains of life and explore organisms with extreme LCD content for different LCD classes. Finally, we illustrate the versatility and specificity achievable with LCD-Composer by identifying diverse classes of LCDs using both simple and multifaceted composition criteria. We demonstrate that the ability to dissect LCDs based on these multifaceted criteria enhances the functional mapping and classification of LCDs. 
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