Så regleras cellens funktion

Tidsperiod: 2021-01-01 till 2024-12-31

Projektledare: Ylva Ivarsson

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 3 200 000 SEK

Phosphorylation and ubiquitination are among the most common post-translational modifications (PTMs) and regulate together most cellular processes. The PTMs are catalyzed by more than 500 kinases and 600 E3 ligases. The substrate specificities of these enzymes are often governed by the recognition of short linear motifs (SLiMs), which are 3-12 amino acid stretches. There is further an intricate crosstalk between phosphorylation and ubiquitination, such that phosphorylation of a degradation motif may regulate the targeting of an E3 ligases to a substrate, and the stability of a kinase can be regulated by an E3 ligase. However, there is a lack fundamental insight into the system, such as which kinases that act on which phosphosites, how E3 ligases are targeted to their substrates, and how the two PTMs crosstalk. Even less is known about how disease-related mutations perturb the system. In this four year project, we will shed light on the SLiM-based interactions of Ser/Thr kinases and E3 ligases and their crosstalk on an unprecedented scale using proteomic peptide phage display, and follow up on selected cases through functional and structural approaches. The project will greatly advance our understanding of the molecular events that underlie cell function, and how the system is affected by disease mutations. The results may in a further perspective be used in the development of novel inhibitors as well as for synthetic biology.