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Abstract Highly expressed proteins tend to evolve slowly, a trend known as the expression level–rate of evolution (E–R) anticorrelation. Whereas the reasons for this anticorrelation remain unclear, the most influential hypotheses attribute it to highly expressed proteins being subjected to strong selective pressures to avoid misfolding and/or misinteraction. In accordance with these hypotheses, work in our laboratory has recently shown that extracellular (secreted) proteins lack an E–R anticorrelation (or exhibit a weaker than usual E–R anticorrelation). Extracellular proteins are folded inside the endoplasmic reticulum, where enhanced quality control of folding mechanisms exist, and function in the extracellular space, where misinteraction is unlikely to occur or to produce deleterious effects. Transmembrane proteins contain both intracellular domains (which are folded and function in the cytosol) and extracellular domains (which complete their folding in the endoplasmic reticulum and function in the extracellular space). We thus hypothesized that the extracellular domains of transmembrane proteins should exhibit a weaker E–R anticorrelation than their intracellular domains. Our analyses of human, Saccharomyces and Arabidopsis transmembrane proteins allowed us to confirm our hypothesis. Our results are in agreement with models attributing the E–R anticorrelation to the deleterious effects of misfolding and/or misinteraction.