Phosphatidylinositol-binding clathrin assembly protein (PICALM)

Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a key adaptor protein facilitating clathrin-mediated endocytosis and membrane trafficking in a broad range of cell types. At the plasma membrane, PICALM recruits clathrin and AP-2 to sites of coated-pit formation, regulates clathrin cage assembly, and thereby influences the internalization of numerous proteins including cell-surface receptors (e.g., transferrin receptor, SNAREs) and synaptic components. PICALM is critical for efficient synaptic vesicle recycling, proper turnover of amyloid precursor protein (APP) fragments, clearance of tau, and overall autophagy, linking it to the pathogenesis of Alzheimer’s disease and related neurodegenerative disorders. Mutations, alternative splicing, or translocations involving PICALM (notably with the MLLT10 gene) contribute to several forms of leukemia and other malignancies. Additionally, PICALM regulates iron homeostasis by facilitating transferrin receptor trafficking and cellular iron uptake—a function essential for cellular proliferation and development. Variants and altered function of PICALM are established risk factors for Alzheimer’s disease, anemia, and hematological cancers. As of 2024, while PICALM is an important disease-associated protein and a candidate for therapeutic targeting, there are no approved drugs that act directly on PICALM.

Other names

CALMCLTHClathrin assembly lymphoid myeloid leukemia proteinLAPMLLT10 fusion partner

Potential: Drugs interfering with clathrin-mediated endocytosis or autophagic pathways could impact PICALM-dependent processes. In MLLT10 (AF10) fusion leukemias, targeting downstream fusion proteins is under investigation. Modulation of iron metabolism via transferrin receptor trafficking could be a route in research settings.