The BARA necessities of PtdIns 3-kinase activation in autophagy

Abstract

Macroautophagy/autophagy is an evolutionarily conserved degradation system with fundamental biological functions. The activation of the class III phosphatidylinositol 3-kinase (PtdIns3K) complexes and the subsequent production of phosphatidylinositol 3-phosphate (PtdIns3P) are pivotal to autophagy. Using a combination of structural biology, biochemistry, and biophysics, we revealed how the non-catalytic subunit BECN1 serves as a membrane-binding switch in the regulation of PtdIns3K complexes and autophagy.

Keywords: Cryoelectron microscopy; HIV; Nef; Rubicon; Tat-BECN1 peptide; human immunodeficiency virus; hydrogen-deuterium exchange.

Figure 1.

Model for regulation of PtdIns3K via the BECN1 BARA domain. The concepts for the activation of PtdIns3K-C2 by RUBCNL, and by RUBCN in LAP, are based on the known presence of the PIKBD in RUBCNL and RUBCN, and the known cellular functions of these proteins. However, the presence of additional membrane targeting domains in RUBCNL and RUBCN is speculative, as is the putative ability of these proteins to target PtdIns3K-C2 to membranes under some conditions.