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These known PtdIns3K activating and inhibiting proteins provide tools for understanding at a structural-mechanistic level how these complexes are switched on and off. In addition, different accessory proteins such as NRBF2 (nuclear receptor binding factor 2), RUBCN/Rubicon, and AMBRA1 bind to the PtdIns3K complexes and positively or negatively regulate their activity. BECN1 is a central node in autophagy regulation. The BARA domain binds to membranes, in part, by inserting an aromatic finger loop into the membrane. Although BECN1 is the smallest subunit within the complex, its C-terminal BARA domain (formerly known as the ‘ECD’) is indispensable for targeting the entire complex to membrane. Structurally, PtdIns3K-C1 and -C2 have essentially the same overall V-shaped architecture, with PIK3C3/VPS34 and PIK3R4/VPS15 forming the catalytic ‘right’ arm of the V, while BECN1 and ATG14-UVRAG form the regulatory ‘left’ arm. PtdIns3K-C1 is critical for autophagy initiation, whereas PtdIns3K-C2 functions in autophagosome maturation, endocytosis, and LC3-associated phagocytosis (LAP). The difference of one subunit determines the specific localization and function of these 2 complexes. PtdIns3K-C1 is composed of PIK3C3/VPS34, PIK3R4/VPS15, BECN1, and ATG14, whereas ATG14 is substituted by UVRAG (UV radiation resistance associated) in PtdIns3K-C2. In mammalian cells, there are 2 heterotetrameric PtdIns3K complexes known as complex I (PtdIns3K-C1) and complex II (PtdIns3K-C2). The PtdIns3K phosphorylates the 3′-position of the inositol head group of PtdIns to generate PtdIns3P, which is essential for the initiation and progression of autophagy. A critical signaling lipid, PtdIns3P, is required for autophagosome formation and maturation. Autophagy maintains cellular homeostasis, and plays important roles in protecting organisms from a variety of diseases, including neurodegenerative disorders, autoimmune diseases, muscle, bone and heart disorders, and cancer. The phagophore matures into an autophagosome, which delivers the cargo to the lysosome for degradation. Autophagy is an essential cellular catabolic process, which is characterized by a transient double-membrane structure called the phagophore, which sequesters cytoplasmic cargoes.