The yin and yang of alternative splicing and short linear motif-based interactions

Short Linear Motifs (SLiMs) are compact modules that provide a spatially efficient solution to encode dynamic, conditional and specific protein interactions. SLiMs control key cellular functions by driving the assembly of dynamic complexes. Deregulation of these interactions are linked to a variety of diseases.

Due to a lack of efficient methods to capture them, SLiMs have become a major blind spot in our understanding of the interactome. To illuminate this blind spot, we pioneered proteomic-peptide phage display.

Here, we will employ the approach to shed light on how alternative splicing of protein coding regions rewire and perturb the SLiM-based interactome.

We will on one hand chart how pre-translational modifications affect interactions of hundreds of protein domains involved in vesicular trafficking, nuclear import/export and protein degradation, and provide quantitative insights into the effects.

On the other hand, we will explore to what extent proteins involved in bringing together the mRNA processing and transporting machinery bind to SLiMs. Key interactions will be studies in detail using structural methods and cell based functional assays.

The project will provide unique insights into the SLiM-based interactome and shed light on how it is perturbed and rewired by pre-translational modifications and how this leads to repurposing of protein function and network rewiring, eventually leading to in to the emergence of new phenotypes in health and disease.