Abstract
Major Intrinsic Proteins (MIPs) are membrane channels that permeate water and other small solutes. Some trypanosomatid MIPs mediate the uptake of antiparasitic compounds, placing them as potential drug targets. However, a thorough study of the diversity of these channels is still missing. Here we place trypanosomatid channels in the sequence-function space of the large MIP superfamily through a sequence similarity network. This analysis exposes that trypanosomatid aquaporins integrate a distant cluster from the currently defined MIP families, here named aquaporin X (AQPX). Our phylogenetic analyses reveal that trypanosomatid MIPs distribute exclusively between aquaglyceroporin (GLP) and AQPX, being the AQPX family expanded in the Metakinetoplastina common ancestor before the origin of the parasitic order Trypanosomatida. Synteny analysis shows how African trypanosomes specifically lost AQPXs, whereas American trypanosomes specifically lost GLPs. AQPXs diverge from already described MIPs on crucial residues. Together, our results expose the diversity of trypanosomatid MIPs and will aid further functional, structural, and physiological research needed to face the potentiality of the AQPXs as gateways for trypanocidal drugs.
Highlights
Major Intrinsic Proteins (MIPs) are membrane channels that permeate water and other small solutes
We show that two MIP families expanded among trypanosomatids: glycerol facilitators or aquaglyceroporins (GLP) and a MIP family previously undescribed as such, named here aquaporin X (AQPX)
We built a sequence similarity network (SSN) to explore where and how kinetoplastid MIPs localize in the superfamily sequencefunction space
Summary
Kinetoplastid MIPs are either GLPs or non-orthodox AQPs. We built a sequence similarity network (SSN) to explore where and how kinetoplastid MIPs localize in the superfamily sequencefunction space. Half of the SSN nodes are from bacteria and the other half from eukaryotes, pointing to an expansion and diversification of the MIP superfamily that is similar in magnitude in both domains of life (Fig. 1b). Holding 80% of the nodes, Cluster 1 has a domain contribution similar to the full network, and the other smaller clusters are almost specific to Bacteria or Eukarya (Fig. 1b). That is the case for the plant XIPs and SIPs, the metazoan AQP11-12 group, algae MIPs (cluster 3, 5, 6, and 9, respectively), and other still uncharacterized divergent clusters (2, 4, 7, 8, and 10) (Fig. 1a).
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