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).
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).