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Abstract

Short linear motifs (SLiMs) are protein interaction sites that play an important role in cell regulation by controlling protein activity, localization, and local abundance. The functionality of a SLiM can be modulated in a context-dependent manner to induce a gain, loss, or exchange of binding partners, which will affect the function of the SLiM-containing protein. As such, these conditional interactions underlie molecular decision-making in cell signaling. We identified multiple types of pre- and posttranslational switch mechanisms that can regulate the function of a SLiM and thereby control its interactions. The collected examples of experimentally characterized SLiM-based switch mechanisms were curated in the freely accessible switches.ELM resource (http://switches.elm.eu.org). On the basis of these examples, we defined and integrated rules to analyze SLiMs for putative regulatory switch mechanisms. We applied these rules to known validated SLiMs, providing evidence that more than half of these are likely to be pre- or posttranslationally regulated. In addition, we showed that posttranslationally modified sites are enriched around SLiMs, which enables cooperative and integrative regulation of protein interaction interfaces. We foresee switches.ELM complementing available resources to extend our knowledge of the molecular mechanisms underlying cell signaling.