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).
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