Cytoplasmic adapter protein that plays a critical role in clathrin-mediated endocytosis which is important in processes such as internalization of cell receptors, synaptic transmission or removal of apoptotic cells. Recruits AP-2 and attaches clathrin triskelions to the cytoplasmic side of plasma membrane leading to clathrin-coated vesicles (CCVs) assembly. Furthermore, regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature. In addition to binding to clathrin, mediates the endocytosis of small R-SNARES (Soluble NSF Attachment Protein REceptors) between plasma membranes and endosomes including VAMP2, VAMP3, VAMP4, VAMP7 or VAMP8. In turn, PICALM-dependent SNARE endocytosis is required for the formation and maturation of autophagic precursors. Modulates thereby autophagy and the turnover of autophagy substrates such as MAPT/TAU or amyloid precursor protein cleaved C-terminal fragment (APP-CTF). Binds to clathrin; involves primarily the C-terminal sequences, but the full-length protein is required for full binding capacity. Binds phosphatidylinositol 4,5- bisphosphate. Interacts with PIMREG; this interaction may change the subcellular location into the nucleus. Interacts with AP2A1 (via its alpha-appendage domain). Interacts (via N-terminus) with VAMP2; VAMP3; VAMP7 and VAMP8 (Via N-terminus). Interacts with LC3/MAP1LC3A. Colocalized with clathrin in the Golgi area. Interaction with PIMREG may target PICALM to the nucleus in some cells. Skins and livers of 1-week-old mice. PICALM-deficient mice suffer from severe anemia due to ineffective erythropoiesis in the bone marrow. In addition, they exhibit impaired clathrin-mediated internalization of transferrin leading to iron metabolism abnormalities. Belongs to the PICALM/SNAP91 family. Truncated N-terminus.