Typically PX domains of sorting nexins, including SNX1 and SNX2 (Cozier et al., 2002; Zhong et al., 2005), play an important role in endosomal membrane recruitment by binding the endosome-enriched lipid PtdIns3P through four conserved residues (Mas et al., 2014; Teasdale and Collins, 2012). These residues are conserved in most PX domains including in SNX1 and SNX2, but are entirely absent in SNX5, SNX6 and SNX32. Although there is evidence for the weak association of the SNX5 PX domain with the lipid PtdIns(4,5)P2 from nuclear magnetic resonance (NMR) spectroscopy experiments (Koharudin et al., 2009), the crystal structure does not point to a clear binding mechanism. A second feature that sets SNX5-related proteins apart from the rest of the SNX family is the presence of an extended α-helical insertion. Our work confirms the central importance of this unique insert for the binding of the IncE inclusion protein, and provides the first clear description of how a PX domain can function as a protein-protein interaction scaffold as opposed to a lipid-binding domain.