The human prostacyclin receptor contains a novel Rab11 binding domain (RBD) that is regulated by palmitoylation

The human prostacyclin receptor (hIP) undergoes agonist‐induced internalization and subsequent recycling involving a direct physical interaction with Rab11a. That interaction localizes to a putative Rab11 binding domain (RBD) within the carboxyl‐terminal (C)‐tail of the hIP. Herein, we sought to define the structural determinants of the RBD and examine the possible role of palmitoylation therein in regulating trafficking of the hIP. Through complimentary approaches in yeast and mammalian cells, the RBD was defined as a 14 residue domain, proximal to transmembrane 7 domain, that is structurally organised into an α‐helix 8 (α‐H8) domain adjacent to the palmitoylated residues at Cys 308 ‐ Cys 311 . Mutational and metabolic labelling studies determined that agonist‐mediated de‐acylation at Cys 309 > Cys 308 and palmitoylation at Cys 311 may dynamically position α‐H8 of the hIP in proximity to Rab11a, to regulate its intracellular trafficking in response to agonist‐stimulation. The identification of a functional role for α‐H8, a common feature of G‐protein coupled receptors, as an RBD as exemplified herein for the hIP is likely to have broader significance for the receptor superfamily. Funded by SFI.