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.
