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. Isoform 2 was found in most tissues examined. Isoform 1 has an overlapping expression pattern but is absent from lung, heart and pancreas. Both isoforms are widely expressed in the brain, higher levels are seen in hippocampus, dentate gyrus, medial habenula nucleus and cerebellar granule cells. Belongs to the PICALM/SNAP91 family.