AP2S1

AP2S1, or adaptor protein complex 2 sigma subunit 1, encodes the sigma-1 subunit of the heterotetrameric AP-2 adaptor complex that mediates clathrin-dependent endocytosis at the plasma membrane. In vertebrates, AP-2 consists of alpha- (AP2A1/2), beta- (AP2B1), mu- (AP2M1), and sigma- (AP2S1) subunits; the sigma subunit participates in assembling and stabilizing the complex and contributes to cargo recognition during endocytosis.

The AP-2 complex binds sorting motifs on cargo proteins and recruits clathrin to form clathrin-coated pits, enabling internalization of receptors and transporters such as the transferrin receptor and various GPCRs. The sigma subunit’s role supports efficient cargo selection and complex assembly, thereby supporting the overall function of clathrin-mediated endocytosis. AP2S1 is broadly expressed and evolutionarily conserved, reflecting the fundamental nature of this endocytic pathway.

Clinical significance: Germline variants in AP2S1 have been linked to familial hypocalciuric hypercalcemia type 3 (FHH3). Pathogenic substitutions, notably at residue Arg15, disrupt interactions between AP-2 and the calcium-sensing receptor (CaSR), impairing CaSR endocytosis and regulation, and leading to elevated serum calcium with reduced urinary calcium excretion. These associations highlight AP2S1’s role in receptor trafficking and calcium homeostasis, while the full spectrum of AP2S1-related conditions continues to be explored.

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