Abstract
Clathrin-mediated endocytosis is a major pathway for the internalization of macromolecules into the cytoplasm of eukaryotic cells. The principle coat components, clathrin and the AP-2 adaptor complex, assemble a polyhedral lattice at plasma membrane bud sites with the aid of several endocytic accessory proteins. Here, we show that huntingtin-interacting protein 1 (HIP1), a binding partner of huntingtin, copurifies with brain clathrin-coated vesicles and associates directly with both AP-2 and clathrin. The discrete interaction sequences within HIP1 that facilitate binding are analogous to motifs present in other accessory proteins, including AP180, amphiphysin, and epsin. Bound to a phosphoinositide-containing membrane surface via an epsin N-terminal homology (ENTH) domain, HIP1 associates with AP-2 to provide coincident clathrin-binding sites that together efficiently recruit clathrin to the bilayer. Our data implicate HIP1 in endocytosis, and the similar modular architecture and function of HIP1, epsin, and AP180 suggest a common role in lipid-regulated clathrin lattice biogenesis.
Highlights
Endocytosis entails the preferential recruitment of select molecules into a patch of plasma membrane that will bud into the cytoplasm
Within the central region of the protein, before the coiled-coil segment, a stretch of three interwoven FX(N/D/ S)X(F/L) motifs proceeds a single DPF triplet (Fig. 1B). This region of huntingtin-interacting protein 1 (HIP1) is quite divergent from HIP1R (Fig. 1B), a related protein roughly 50% identical to HIP1 that localizes to clathrin-coated pits [28]
HIP1R colocalizes more precisely with clathrin and with AP-2 in several cell types [28], and the link between the HIP protein family and endocytosis is validated by Sla2p, the S. cerevisiae orthologue of HIP1/HIP1R
Summary
Endocytosis entails the preferential recruitment of select molecules into a patch of plasma membrane that will bud into the cytoplasm. We show that huntingtin-interacting protein 1 (HIP1), a binding partner of huntingtin, copurifies with brain clathrin-coated vesicles and associates directly with both AP-2 and clathrin. The discrete interaction sequences within HIP1 that facilitate binding are analogous to motifs present in other accessory proteins, including AP180, amphiphysin, and epsin.
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