Linear motifs regulating protein secretion, sorting and autophagy in Leishmania parasites are diverged with respect to their host equivalents

The pathogenic, tropical Leishmania flagellates belong to an early-branching eukaryotic lineage (Kinetoplastida) with several unique features. Unfortunately, they are poorly understood from a molecular biology perspective, making development of mechanistically novel and selective drugs difficult. Here, we explore three functionally critical targeting short linear motif systems as well as their receptors in depth, using a combination of structural modeling, evolutionary sequence divergence and deep learning. Secretory signal peptides, endoplasmic reticulum (ER) retention motifs (KDEL motifs), and autophagy signals (motifs interacting with ATG8 family members) are ancient and essential components of cellular life. Although expected to be conserved amongst the kinetoplastids, we observe that all three systems show a varying degree of divergence from their better studied equivalents in animals, plants, or fungi. We not only describe their behaviour, but also build models that allow the prediction of localization and potential functions for several uncharacterized Leishmania proteins. The unusually Ala/Val-rich secretory signal peptides, endoplasmic reticulum resident proteins ending in Asp-Leu-COOH and atypical ATG8-like proteins are all unique molecular features of kinetoplastid parasites. Several of their critical protein-protein interactions could serve as targets of selective antimicrobial agents against Leishmaniasis due to their systematic divergence from the host. Leishmaniasis is a detrimental disease which causes significant decrease in quality of life and in severe cases can be lethal. The disease is caused by the pathogen Leishmania spread by sandfly vectors with vertebrates (including humans) being the primary hosts. Leishmaniasis affects over 10 million people worldwide, with ongoing environmental warming being considered to be helping the disease to spread to new regions. Leishmania pathogenesis is currently poorly understood and to combat the infection and to better control the disease further insights into molecular details of the pathogen are needed. Here we describe three protein sorting systems critical for Leishmania cellular housekeeping and infection processes that are greatly diverged from their host counterparts: secretory signal peptides, endoplasmic reticulum retention motifs, and autophagy signals. We provide state-of-the-art computational models to illuminate these systems. Exploring these major cellular sorting motifs may provide new insights into Leishmania cell biology and aid in developing novel therapeutics.