Fast friends – Ubiquitin-like modifiers as engineered fusion partners

Ubiquitin and its relatives are major players in many biological pathways, and a variety of experimental tools based on biological chemistry or protein engineering is available for their manipulation. One popular approach is the use of linear fusions between the modifier and a protein of interest. Such artificial constructs can facilitate the understanding of the role of ubiquitin in biological processes and can be exploited to control protein stability, interactions and degradation. Here we summarize the basic design considerations and discuss the advantages as well as limitations associated with their use. Finally, we will refer to several published case studies highlighting the principles of how they provide insight into pathways ranging from membrane protein trafficking to the control of epigenetic modifications. [Display omitted] •Flexible tethering facilitates the use of ubiquitin-like proteins in linear fusions.•Linear fusions are widely used to study the functions of ubiquitin-like modifiers.•Linear ubiquitin fusions can be used to control protein stability and degradation.