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1.C.127.  The Pore-forming Trypanolytic Apolipoprotein A1 Factor (APOL1) Family 

Apolipoprotein L-1 (APOL1), the trypanolytic factor of human serum, can lyse several African trypanosome species including Trypanosoma brucei brucei, but not the human-infective pathogens T. brucei rhodesiense and T. brucei gambiense, which are resistant to lysis by human serum. Lysis follows the uptake of APOL1 into acidic endosomes and is apparently caused by colloid-osmotic swelling due to increased ion permeability of the plasma membrane. Thomson and Finkelstein 2015 demonstrated that nanogram quantities of full-length recombinant APOL1 cause the formation of cation-selective macroscopic conductances in planar lipid bilayers. The conductances are highly sensitive to pH: their induction required acidic pH (pH 5.3), but their magnitude could be increased 3,000-fold upon alkalinization of the milieu (pKa = 7.1). This conductance was attributed to the association of APOL1 with the bilayer at acidic pH, followed by the opening of APOL1-induced cation-selective channels upon pH neutralization. Furthermore, the conductance increase at neutral pH (but not membrane association at acidic pH) was prevented by the interaction of APOL1 with the serum resistance-associated protein, which is produced by T. brucei rhodesiense (Q8T309) and prevents trypanosome lysis by APOL1. Thus, lysis involves endocytic recycling of APOL1 and the formation of cation-selective channels at neutral pH in the parasite plasma membrane (Thomson and Finkelstein 2015). 

APOL1 is the channel-forming component necessary for innate immunity. The common human APOL1 variant G0 provides protection against infection with certain Trypanosoma and Leishmania parasite species, but it cannot protect against the trypanosomes responsible for human African trypanosomiasis. Human APOL1 variants G1 and G2 protect against human-infective trypanosomes, but also confer a higher risk of developing chronic kidney disease. Trypanosome-killing activity is dependent on the ability of APOL1 to insert into membranes at acidic pH and form pH-gated cation channels. Coiled-coil binding of the leucine zipper domains of APOL1 is necessary for the open cation channel conformation (Schaub et al. 2021).

This family includes two distantly related sub-families (1.C.127.1, exclusively from animals, with no homologues in other eukaryotes), and subfamily 1.C.127.2 (exclusively from bacteria).  Further, these proteins all appear to be distantly related to the pore-forming constituents of TC family 1.C.36, especiallly sub-family 1.C.36.3. Family 1.C.36 includes proteins that form pores in host animal cell plasma membranes in conjunction with Type III protein secretion systems of bacteria. The proposed relationships between these families are not yet fully established but are under investigation (M Saier, preliminary observations).

References associated with 1.C.127 family:

Carney, E.F. (2019). APOL1 risk variants induce opening of the mitochondrial permeability transition pore. Nat Rev Nephrol 15: 730. 31602044
Schaub, C., J. Verdi, P. Lee, N. Terra, G. Limon, J. Raper, and R. Thomson. (2020). Cation channel conductance and pH gating of the innate immunity factor APOL1 is governed by pore lining residues within the C-terminal domain. J. Biol. Chem. [Epub: Ahead of Print] 32727852
Schaub, C., P. Lee, A. Racho-Jansen, J. Giovinazzo, N. Terra, J. Raper, and R. Thomson. (2021). Coiled-coil binding of the leucine zipper domains of APOL1 is necessary for the open cation channel conformation. J. Biol. Chem. 101009. [Epub: Ahead of Print] 34331942
Thomson, R. and A. Finkelstein. (2015). Human trypanolytic factor APOL1 forms pH-gated cation-selective channels in planar lipid bilayers: relevance to trypanosome lysis. Proc. Natl. Acad. Sci. USA 112: 2894-2899. 25730870