Coevolution of secreted proteins and members of the secretory pathway reveals interactions and motifs used for proper secretion

The secretory pathway consists of hundreds of macromolecules that function by physically interacting with and modifying secreted proteins to bring them to their final form and location. These include include chaperones, translocases, and enzymes for post‐translational modifications. Some of these are generic proteins for maintaining homeostasis in the secretory pathway, while others are specific for processing groups or individual secreted proteins. Additionally, many of these machinery come from common families that are conserved across eukaryotes. Understanding how these proteins are able to process thousands of secreted proteins across organisms and cell types is important and still lack fine‐grained details. In this study, we take an evolutionary approach to systematically characterize interactions between secreted proteins and the machinery proteins. Using mutual information and directed coupling analysis, we discover amino acids between pairs of proteins that have coevolved. We use this to predict interactions between proteins and compare them to the literature as well as computationally predicted database PrePPI. Additionally, we discover functional amino acid motifs within this pathway seen across organisms. By examining regions not found in the most conserved regions, this technique can capture previously unknown functional residues. This approach adds to work done in prokaryotes, here showing that interactions can be inferred between proteins in the secretory pathway by studying their amino acid content. Support or Funding Information Novo Nordisk Foundation