Proteome-Scale Relationships Between Local Amino Acid Composition and Protein Fates and Functions

Abstract Proteins with low-complexity domains continue to emerge as key players in both normal and pathological cellular processes. Although low-complexity domains are often grouped into a single class, individual low-complexity domains can differ substantially with respect to amino acid composition. These differences may strongly influence the physical properties, cellular regulation, and molecular functions of low-complexity domains. Therefore, we developed a bioinformatic approach to explore relationships between amino acid composition, protein metabolism, and protein function. We find that local compositional enrichment within protein sequences affects the translation efficiency, abundance, half-life, subcellular localization, and molecular functions of proteins on a proteome-wide scale. However, these effects depend upon the type of amino acid enriched in a given sequence, highlighting the importance of distinguishing between different types of low-complexity domains. Furthermore, many of these effects are discernible at amino acid compositions below those required for classification as low-complexity or statistically-biased by traditional methods and in the absence of homopolymeric amino acid repeats, indicating that thresholds employed by classical methods may not reflect biologically relevant criteria. Application of our analyses to composition-driven processes, such as the formation of membraneless organelles, reveals distinct composition profiles even for closely related organelles. Collectively, these results provide a unique perspective and detailed insights into relationships between amino acid composition, protein metabolism, and protein functions. Author Summary Low-complexity domains in protein sequences are regions that are composed of only a few amino acids in the protein “alphabet”. These domains often have unique chemical properties and play important biological roles in both normal and disease-related processes.While a number of approaches have been developed to define low-complexity domains, these methods each possess conceptual limitations. Therefore, we developed a complementary approach that focuses on local amino acid composition (i.e. the amino acid composition within small regions of proteins). We find that high local composition of individual amino acids is associated with pervasive effects on protein metabolism, subcellular localization, and molecular function on a proteome-wide scale. Importantly, the nature of the effects depend on the type of amino acid enriched within the examined domains, and are observable in the absence of classically-defined low-complexity (and related) domains. Furthermore, we define the compositions of proteins involved in the formation of membraneless, protein-rich organelles such as stress granules and P-bodies. Our results provide a coherent view and unprecedented resolution of the effects of local amino acid enrichment on protein biology.