Collaborative internship proposed with: Brenda Andrews
Proteins contain intrinsically disordered regions - they consist of protein sequences with no apparent structure under native conditions. Although rare in bacteria and archaea, these regions are prevalent in eukaryotes. For example, they populate roughly 15-20% of the proteins in our genome. Their role is not fully understood, however, they are thought to be enriched in protein regulatory elements or short linear motifs. These short linear motifs are critical for the function of proteins as they act as functional switches which modulate the location, activity and degradation of the protein. The goal of my project is to perform a systematic genome-wide prediction of short linear motifs using evolutionary conservation.
I will begin by collecting several characterized instances of short linear motifs, including phosphorylation sites, localization signals, interaction motifs and degradation signals. These short linear motifs will be examined for their evolutionary properties and used to design a phylogenetic hidden Markov Model. This algorithm can assess evolutionary conservation by taking advantage of the phylogenetic tree between species. I will then perform a genome-wide search for short conserved sequences. This search will uncover novel short linear motifs and interesting conserved sequences will be functionally assayed in the lab by performing single-site mutagenesis on the predicted sequences. Another aspect of this project is to use the predicted sequences to uncover amino acid patterns which define short linear motifs. While several patterns are known to the scientific community, it is estimated that many more exist. I have already shown that evolutionary conservation alone is sufficient in uncovering the pattern specificity of two kinases. By grouping the predicted short linear motifs using sequence similarity, novel patterns will be discovered and function can be deduced. I will test if the patterns are directly responsible for the inferred function.