The clathrin heavy chain (Chc) is a crucial component of the clathrin protein complex, which plays a central role in clathrin-mediated endocytosis, a fundamental cellular process for internalizing various cargoes such as membrane proteins, nutrients, and even pathogens. With a molecular weight of approximately 190 kDa, the clathrin heavy chain forms a triskelion structure along with three clathrin light chains, providing the structural backbone of the clathrin lattice. This lattice can form cages of different sizes and shapes, essential for the invagination and excision of vesicles during endocytosis. The clathrin heavy chain contains 145-residue repeats known as Clathrin Heavy Chain Repeats, which fold into elongated superhelical structures and define distinct domains, including the proximal, knee, distal, and ankle domains. Its N-terminal domain (NTD) adopts a WD40 beta-propeller structure and is vital for interacting with various adaptor proteins (APs) that link the clathrin scaffold to the membrane. These interactions are mediated through multiple binding sites, or "boxes," on the NTD, including the Clathrin box, W-box, and Arrestin box, each recognizing specific motifs on the adaptor proteins.