Unconventional mechanism of autoregulation of membrane binding by the PH-FYVE tandem domains of Phafin2

Phafin2 is a peripheral protein involved in membrane-dependent functions, including endosomal cargo trafficking, apoptosis, macropinocytosis, and autophagy. The multiple functions of Phafin2 are associated with its ability to bind membrane phosphoinositide phosphatidylinositol 3-phosphate (PtdIns3P) through both its PH and FYVE domains. However, the molecular mechanism underlying dual PtdIns3P contacts by Phafin2 remains to be determined. Our recent studies discovered a conserved poly aspartic (polyD) motif (240-DDDDDDDSSD-249) at the C-terminus of Phafin2, which specifically downregulates binding of the PH domain to PtdIns3P.