9.B.188 The Transmembrane Emp24 Domain-containing Protein (TMED) Family 

Members of this family are involved in vesicular protein trafficking and mainly function in the early secretory pathway, but also in post-Golgi membranes. It is thought to act as a cargo receptor at the lumenal side for incorporation of secretory cargo molecules into transport vesicles and to be involved in vesicle coat formation at the cytoplasmic side. In COPII vesicle-mediated anterograde transport, it is involved in the transport of GPI-anchored proteins and is proposed to act together with TMED10 as a cargo receptor; the function specifically implies SEC24C and SEC24D of the COPII vesicle coat and lipid raft-like microdomains of the ER. It recognizes GPI anchors , structurally remodeled in the ER by PGAP1 and MPPE1. COPI vesicle-mediated retrograde transport inhibits the GTPase-activating activity of ARFGAP1 towards ARF1, thus preventing immature uncoating and allowing cargo selection to take place. It is involved in trafficking of G protein-coupled receptors (GPCRs). It regulates F2RL1, OPRM1 and P2RY4 exocytic trafficking from the Golgi to the plasma membrane, thus contributing to receptor resensitization, and it facilitates CASR maturation and stabilization in the early secretory pathway while increasing CASR plasma membrane targeting. It has been proposed to be involved in the organization of intracellular membranes such as the maintenance of the Golgi apparatus and may play a role in the biosynthesis of secreted cargo, i.e., eventual processing (Beck et al. 2009). The p24/transmembrane emp24 domain (TMED) family of cargo receptors has been shown to be important in development and disease and has been reviewed (Aber et al. 2019).

The transmembrane emp24 domain-containing (TMED) proteins, also called p24 proteins, are members of a family of sorting receptors present in all representatives of the Eukarya and abundantly present in all subcompartments of the early secretory pathway, namely the endoplasmic reticulum (ER), the Golgi, and the intermediate compartment. It is essential during the bidirectional transport between the ER and the Golgi. Mota et al. 2021 described the high-resolution structure of a TMED1 Golgi Dynamics (GOLD) representative and its biophysical characterization in solution. The crystal structure showed  dimer formation that is present in solution in a salt-dependent manner, suggesting that the GOLD domain can form homodimers in solution, even in the absence of the TMED1 coiled-coil region.