20 November 2020
Julie Forman-Kay
Research Institute of the Hospital for Sick Children and
Department of Biochemistry, University of Toronto
Intrinsically disordered regions make up a large part of the proteome, but it is challenging to understand sequence-to-function relationships, partly due to inability to align primary amino acid sequences of these regions. Together with Alan Moses, we are developing an approach to identify molecular features preserved in the amino acid sequences of orthologous intrinsically disordered regions, creating a different definition of "conservation" and opening up the potential for predicting function for disordered regions from their amino acid sequences. Some of the conserved features relate to physicochemical properties associated with phase separation, a process now appreciated to facilitate cellular organization, regulation and biomaterial formation.
It is similarly challenging to understand how disease mutations in disordered regions impact pathology, since many bioinformatic tools rely on positional alignment and predictions assuming folded protein structure. Thus, these mutations are frequently neglected or annotated as variants of unknown significance, despite their prevalence in disease. We propose that IDRs involved in phase separation are vulnerable to disease mutations, as we find predicted phase separation propensities enriched in proteins associated with cancer and neurological disorders and IDRs are involved in regulatory phase separation in many critical cellular processes.
Experimental work in our lab provides evidence for disordered protein region phase separation regulating protein translation and RNA deadenylation by differential partitioning of molecules and protein "solvent" effects on enzyme kinetics, reinforcing the growing list of "functions" of IDRs and biological phase separation. Protein bioinformatics tools that address IDR features and phase separation should thus be valuable for a broader understanding of protein function and disease.