Figure 2.

Scenarios for issues of heterologous rescue results. (A) D. melanogaster wild-type protein dPOI^WT encoded by a dGOI has a local interactome, represented by the interacting proteins dIP1, dIP2 and dIP3. When these four proteins interact correctly, the resulting functional complex supports a normal phenotype (top). The functional domain of dPOI^WT is D1, which is also present in different hPOI^WT equivalents (bottom); some of these equivalents have additional functional domains D2 and D3. (B) hPOI^WT allows heterologous rescue (top) or has a steric conformation leading to a loose interaction with dIP2. This condition either prevents formation of the functional complex (no heterologous rescue) or leads to an unstable complex, which determines a partial heterologous rescue result. (C) The normal pathway in humans involves supplemental interactions among hPOI^WT, hIP1 and hIP2 (top); D1 of hPOI^WT may rescue the phenotype (bottom), but if D2 is defect in patients, chemical repair of D1 in fruit flies drives to a positive heterologous result which cannot be extrapolated to patients. (D) A distinct way to ensemble the functional complex in humans, when the interactome was not evolutionary conserved (upper). hPOI^WT has supplemental domains D3 and D4; in this case, D4 domain sterically prevents the proper interaction of D1 with dIP1, therefore heterologous rescue intrinsically fails (bottom). Created with BioRender.com (accessed on 23 February 2022).