Specificity determinants for PTM modifying enzymes in the Nilsson Lab

 Regulation of protein activity by PTMs is a major regulatory mechanism. Despite tremendous progress in identification of PTMs the fundamental principles regulating their addition or removal are poorly understood. An emerging concept for many PTM modifying enzymes is that SLiMs in substrates or substrate specifiers confer specificity. Identification and characterization of these SLiMs therefore provides important insight into PTM modifying enzymes.

”Our aim is to bring the study of protein phosphatases and ubiquitin ligases from the realm of passive observation to a situation where precise engineering of signaling pathways is possible,” says Professor and Group Leader Jakob Nilsson.

The group has uncovered general principles of substrate selection for the PP2A-B56 phosphatase (Hertz et al, Mol Cell 2016) and PP4 (Ueki et al, Mol Cell 2019). This work has shown that short linear motifs (SLiMs) are key determinants of specificity for phosphatases and that these interactions are regulated by phosphorylation of the SLiMs. A careful characterization of SLiMs allows for a system wide understanding of pathways regulated by protein phosphatases. “In addition to providing a full picture of pathways regulated by phosphatases SLiM mediated interactions are also ideal targets for small molecule inhibitors and we are actively pursuing this to develop the first class of specific inhibitors” says Jakob Nilsson.

 The group has recently expanded these efforts to identify SLiMs that confer specificity to ubiquitin ligases as part of the UBIMOTIF network (https://ubimotif.ku.dk). SLiMs are often recognized by ubiquitin ligases to target a protein for degradation which is exploited in PROTAC technologies. Identifying SLiMs for ubiquitin ligases has the potential to expand the applications of PROTAC technologies.