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. Author manuscript; available in PMC: 2016 May 1.
Published in final edited form as: Semin Nephrol. 2015 May;35(3):222–236. doi: 10.1016/j.semnephrol.2015.04.008

Figure 4. APOL1 domain organization and proposed mechanisms of APOL1 trypanolysis.

Figure 4

Panel A shows the domain structure suggested by Pays and colleagues, identical that shown in figure 1. Panel B shows the model of APOL1 trypanolysis proposed by Pays and colleagues. In this model the HDL-bound APOL1 is endocytosed by the trypanosome and trafficked to the trypanosome lysosome. Once in the lysosome, the acidic environment leads to opening of the hairpin-like membrane-addressing domain, followed by dissociation of APOL1 from the HDL particle and insertion membrane-addressing domain into the lysosomal membrane. The pore-forming domain of APOL1 forms a chloride channel that depolarizes the lysosomal membrane, leading to irreversible swelling of the lysosome, followed by trypanolysis. SRA inhibits APOL1 within the lysosome by binding the SRA-interacting domain on APOL1, though the mechanism of inhibition is unclear. Panel C depicts the model of trypanolysis proposed by Thomson and Finkelstein. In this model, following endocytosis and trafficking to the lysosome, the acidic environment leads to irreversible insertion of APOL1 into the lysosomal membrane, a process mediated by the SRA-interacting domain. The APOL1 channel is inactive until recycled to the trypanosome cell surface, where neutral pH leads to APOL1 channel activation. Cation influx through APOL1 depolarizes the plasma membrane and is coupled to potassium efflux and anion and water influx, followed by loss of osmoregulation, cytoplasmic vacuolization, and lysis. SRA binding to APOL1 is speculated to inhibit insertion of the SRA-interacting domain into the lysosomal membrane, thereby preempting APOL1 channel formation and lysis. Panel D depicts a revised model for APOL1 domain organization. The pore-forming domain has been removed, as the residues responsible for channel formation remain to be identified. The membrane-addressing domain has been replaced by a proposed membrane insertion domain at the C terminus, within the SRA-interacting domain. PF, pore-forming domain. MA, membrane-addressing domain. SI,SRA-interacting domain. Other abbreviations as in Figure 1. [Permission pending from Pays et al., Nat Rev Microbiol. 2006, PMID: 16710327; Thomson and Finkelstein, Proc Natl Acad Sci U S A. 2015PMID: 25730870]