ATG3
Domain
The N-terminal region works in concert with its geometry-selective amphipathic helix (AH) to promote LC3-PE conjugation activity only on the target membrane.
The LC3 interacting regions (LIR) motif mediates interaction with GABARAP and MAP1LC3A in a beta-sheet conformation-dependent manner (PubMed:37252361). The LIR motif is required for LC3 lipidation and ATG3~LC3 thioester formation (PubMed:37252361).
The membrane-curvature-sensing motif targets curved membranes.
Function
E2 conjugating enzyme that catalyzes the covalent conjugation of the C-terminal Gly of ATG8-like proteins (GABARAP, GABARAPL1, GABARAPL2 or MAP1LC3A) to the amino group of phosphatidylethanolamine (PE)-containing lipids in the membrane resulting in membrane-bound ATG8-like proteins which is one of the key steps in the development of autophagic isolation membranes during autophagosome formation (PubMed:24191030, PubMed:33446636, PubMed:37252361). Cycles back and forth between binding to ATG7 for loading with the ATG8-like proteins and binding to E3 enzyme, composed of ATG12, ATG5 and ATG16L1 to promote ATG8-like proteins lipidation (PubMed:11825910, PubMed:12207896, PubMed:12890687, PubMed:16704426, PubMed:24186333). Also plays a role as a membrane curvature sensor that facilitates LC3/GABARAP lipidation by sensing local membrane stress associated with lipid-packing defects as occurs with high molar proportions of conical lipids or strident membrane curvature (By similarity). Interacts with negatively-charged membranes promoting membrane tethering and enhancing LC3/GABARAP lipidation (PubMed:29142222). Also acts as an autocatalytic E2-like enzyme by catalyzing the conjugation of ATG12 to itself in an ATG7-dependent manner, this complex thus formed, plays a role in mitochondrial homeostasis but not in autophagy (By similarity). ATG12-ATG3 conjugation promotes late endosome to lysosome trafficking and basal autophagosome maturation via its interaction with PDCD6IP (By similarity). ATG12-ATG3 conjugate is also formed upon viccina virus infection, leading to the disruption the cellular autophagy which is not necessary for vaccinia survival and proliferation (By similarity). Promotes primary ciliogenesis by removing OFD1 from centriolar satellites via the autophagic pathway (By similarity).
Post-translational modifications
Cleaved by CASP8 upon death ligand binding such as tumor necrosis factor-alpha (PubMed:22644571). CASP8 cleavage blocks survival-related autophagy and favors apoptosis (PubMed:22644571).
Conjugated to ATG12 at Lys-243. ATG12-conjugation plays a role in regulation of mitochondrial homeostasis and cell death, while it is not involved in phosphatidylethanolamine-conjugation to ATG8-like proteins and autophagy.
Sequence Similarities
Belongs to the ATG3 family.
Tissue Specificity
Widely expressed, with a highest expression in heart, skeletal muscle, kidney, liver and placenta.
Cellular localization
- Cytoplasm
Alternative names
APG3, APG3L, ATG3, Ubiquitin-like-conjugating enzyme ATG3, Autophagy-related protein 3, Protein PC3-96, APG3-like, hApg3