Nutrient transporters can be rapidly removed from cell surface via substrate-stimulated endocytosis as a way to control nutrient influx, but the molecular underpinnings have not been well understood. In this work, we focused on zinc-dependent endocytosis of human ZIP4 (hZIP4), a zinc transporter essential for dietary zinc uptake. Structure-guided mutagenesis and internalization assay revealed that hZIP4 per se acts as the exclusive zinc sensor with the transport site being responsible for zinc sensing. In an effort of seeking sorting signal, a scan of the longest cytosolic loop (L2) led to identification of a conserved LQL motif essential for endocytosis. Partial proteolysis of purified hZIP4 demonstrated a structural coupling between the transport site and the L2 upon zinc binding, which supports a working model of how zinc ions at physiological concentration trigger a conformation-dependent endocytosis of the zinc transporter. This work provides a new paradigm on post-translational regulation of nutrient transporters.

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