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 (PubMed:10436022, PubMed:16262731, PubMed:27574975). Furthermore, regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature (PubMed:25898166). 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 (PubMed:22118466, PubMed:21808019, PubMed:23741335). In turn, PICALM-dependent SNARE endocytosis is required for the formation and maturation of autophagic precursors (PubMed:25241929). Modulates thereby autophagy and the turnover of autophagy substrates such as MAPT/TAU or amyloid precursor protein cleaved C-terminal fragment (APP-CTF) (PubMed:25241929, PubMed:24067654). 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 (PubMed:16491119). Interacts with AP2A1 (via its alpha-appendage domain) (PubMed:16262731). Interacts (via N-terminus) with VAMP2; VAMP3; VAMP7 and VAMP8 (Via N-terminus) (PubMed:22118466, PubMed:21808019, PubMed:23741335). Interacts with LC3/MAP1LC3A (PubMed:24067654). Colocalized with clathrin in the Golgi area (PubMed:10436022). Interaction with PIMREG may target PICALM to the nucleus in some cells (PubMed:16491119). Expressed in all tissues examined. A chromosomal aberration involving PICALM is found in diffuse histiocytic lymphomas. Translocation t(10;11)(p13;q14) with MLLT10. Belongs to the PICALM/SNAP91 family. Extended N-terminus.