MTSviewer: a database to visualize mitochondrial targeting sequences, cleavage sites, and mutations on protein structures

Abstract

AbstractMitochondrial dysfunction is implicated in a wide array of human diseases ranging from neurodegenerative disorders to cardiovascular defects. The coordinated localization and import of proteins into mitochondria is an essential process that ensures mitochondrial homeostasis and consequently cell survival. The localization and import of most mitochondrial proteins are driven by N-terminal mitochondrial targeting sequences (MTS), which interact with import machinery and are removed by the mitochondrial processing peptidase (MPP). The recent discovery of internal MTS’s - those which are distributed throughout a protein and act as import regulators or secondary MPP cleavage sites – has expanded the role of both MTS’s and MPP beyond conventional N-terminal regulatory pathways. Still, the global mutational landscape of MTS’s remains poorly characterized, both from genetic and structural perspectives. To this end, we have integrated a variety of prediction tools into one harmonized R/Shiny database called MTSviewer, which combines MTS predictions, MPP cleavage sites, genetic variants, pathogenicity predictions, and N-terminomics data with structural visualization using AlphaFold models. Using this platform, we have generated a list of disease-linked variants in protein MTS’s and their predicted consequences as a resource for their functional characterization. Overall, MTSviewer is a platform that can be used to interrogate MTS mutations and their potential effects on import and proteolysis across the mitochondrial proteome.