Using detailed functional studies on 24 human transferrln receptor mutants, we identified YXRF as the internallxatlon sequence. Provided that at least 7 residues separate this tetmpeptkfe from the tmnsmembrane region, changing the tetmpeptlde position within the TR cytoplasmlc domaln does not reduce internallzatlon activity. Thus, any conformatlonal determinant for internalization must be localized to the YXRF sequence. Wenty-elght tetrapeptide analogs of YXRF, found by an unbla8ed search of all known thme-dlmenslonal proteln structures, significantly favored tight turns similar to a type I turn. Of the ten tetrapep tides most closely related to YXRF, eight were surface exposed and had tight-turn conformations, as were four of fhfe tetmpeptldes with sequences related to the low density lipoprotein receptor internallxation motif, NPXY. The internalization sequences of both receptors contain aromatic residues with intervening hydrogen-bonding residues. Thus, two distinct internallzation sequences favor a common structural chemistry and Implicate an exposed tlght turn as the recognition motif for high efficiency endocytosls.