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. 

 


 

References:

Aber, R., W. Chan, S. Mugisha, and L.A. Jerome-Majewska. (2019). Transmembrane emp24 domain proteins in development and disease. Genet Res (Camb) 101: e14.

Bartoszewski, S., S. Luschnig, I. Desjeux, J. Grosshans, and C. Nüsslein-Volhard. (2004). Drosophila p24 homologues eclair and baiser are necessary for the activity of the maternally expressed Tkv receptor during early embryogenesis. Mech Dev 121: 1259-1273.

Carney, G.E. and N.J. Bowen. (2004). p24 proteins, intracellular trafficking, and behavior: Drosophila melanogaster provides insights and opportunities. Biol Cell 96: 271-278.

Chen, F., H. Hasegawa, G. Schmitt-Ulms, T. Kawarai, C. Bohm, T. Katayama, Y. Gu, N. Sanjo, M. Glista, E. Rogaeva, Y. Wakutani, R. Pardossi-Piquard, X. Ruan, A. Tandon, F. Checler, P. Marambaud, K. Hansen, D. Westaway, P. St George-Hyslop, and P. Fraser. (2006). TMP21 is a presenilin complex component that modulates γ-secretase but not ε-secretase activity. Nature 440: 1208-1212.

Feng, L., P. Cheng, Z. Feng, and X. Zhang. (2022). Transmembrane p24 trafficking protein 2 regulates inflammation through the TLR4/NF-κB signaling pathway in lung adenocarcinoma. World J Surg Oncol 20: 32.

Hou, W. and L.A. Jerome-Majewska. (2018). TMED2/emp24 is required in both the chorion and the allantois for placental labyrinth layer development. Dev Biol 444: 20-32.

Hou, W., S. Gupta, M.C. Beauchamp, L. Yuan, and L.A. Jerome-Majewska. (2017). Non-alcoholic fatty liver disease in mice with heterozygous mutation in TMED2. PLoS One 12: e0182995.

Kondylis, V., Y. Tang, F. Fuchs, M. Boutros, and C. Rabouille. (2011). Identification of ER proteins involved in the functional organisation of the early secretory pathway in Drosophila cells by a targeted RNAi screen. PLoS One 6: e17173.

Li, X., Y. Wu, C. Shen, T.Y. Belenkaya, L. Ray, and X. Lin. (2015). Drosophila p24 and Sec22 regulate Wingless trafficking in the early secretory pathway. Biochem. Biophys. Res. Commun. 463: 483-489.

Luo, W., Y. Wang, and G. Reiser. (2011). Proteinase-activated receptors, nucleotide P2Y receptors, and μ-opioid receptor-1B are under the control of the type I transmembrane proteins p23 and p24A in post-Golgi trafficking. J Neurochem 117: 71-81.

Mota, D.C.A.M., I.A. Cardoso, R.M. Mori, M.R.B. Batista, L.G.M. Basso, M.C. Nonato, A.J. Costa-Filho, and L.F.S. Mendes. (2021). Structural and thermodynamic analyses of human TMED1 (p24γ1) Golgi dynamics. Biochimie. [Epub: Ahead of Print]

Nie, Z.W., Y.J. Niu, W. Zhou, D.J. Zhou, J.Y. Kim, and X.S. Cui. (2020). AGS3-dependent TGN-membrane trafficking is essential for compaction in mouse embryos. J Cell Sci. [Epub: Ahead of Print]

Pardossi-Piquard, R., C. Böhm, F. Chen, S. Kanemoto, F. Checler, G. Schmitt-Ulms, P. St George-Hyslop, and P.E. Fraser. (2009). TMP21 transmembrane domain regulates γ-secretase cleavage. J. Biol. Chem. 284: 28634-28641.

Salnikov, E.S., C. Aisenbrey, B. Pokrandt, B. Brügger, and B. Bechinger. (2019). Structure, Topology, and Dynamics of Membrane-Inserted Polypeptides and Lipids by Solid-State NMR Spectroscopy: Investigations of the Transmembrane Domains of the DQ Beta-1 Subunit of the MHC II Receptor and of the COP I Protein p24. Front Mol Biosci 6: 83.

Xu, X., H. Gao, J. Qin, L. He, and W. Liu. (2015). TMP21 modulates cell growth in papillary thyroid cancer cells by inducing autophagy through activation of the AMPK/mTOR pathway. Int J Clin Exp Pathol 8: 10824-10831.

Zhang, X., H.H. Hao, H.W. Zhuang, J. Wang, Y. Sheng, F. Xu, J. Dou, C. Chen, and Y. Shen. (2022). Circular RNA circ_0008305 aggravates hepatocellular carcinoma growth through binding to miR-186 and inducing TMED2. J Cell Mol Med 26: 1742-1753.

Examples:

TC#NameOrganismal TypeExample
9.B.188.1.1

The transmembrane (2 TMSs, N- and C-termini) Emp24 domain-containing protein 1, TMED1 of 227 aas.

Animals

TMED1 of Homo sapiens

 
9.B.188.1.2

The transmembrane (2 TMSs, N- and C-termini) Emp24 domain-containing protein 2, TMED2 or RNP24 of 201 aas. A role for TMED2 in liver health has been suggested (Hou et al. 2017). The structure, topology, and dynamics of membrane-inserted polypeptides and lipids have been examined by solid-state NMR spectroscopy, specifically with respect to the transmembrane domains of the DQ Beta-1 subunit of the MHC II receptor and the COP I protein, p24 (Salnikov et al. 2019). The role of the p24/transmembrane emp24 domain (TMED) family of cargo receptors in development and disease has been reviewed (Aber et al. 2019). TMED2/emp24 is required in both the chorion and the allantois for placental labyrinth layer development involving membrane fusion (Hou and Jerome-Majewska 2018). Circular RNA circ_0008305 aggravates hepatocellular carcinoma growth through binding to miR-186 and inducing TMED2 (Zhang et al. 2022).

Animals

TMED2 of Homo sapiens

 
9.B.188.1.3

The transmembrane (2 TMSs, N- and C-termini) Emp24 domain-containing protein 3, TMED3 of 217 aas.

Animals

TMED3 of Homo sapiens

 
9.B.188.1.4

Transmembrane emp24 domain-containing protein 10 precursor, Tmed10 or TMP21, of 219 aas and 2 TMSs, N- and C-terminal. It is involved in vesicular protein trafficking in the early secretory pathway, probably as a cargo receptor at the lumenal side for incorporation of secretory cargo molecules into transport vesicles (Luo et al. 2011). The TMP21 transmembrane domain promotes its association with the presenilin complex that results in decreased gamma-cleavage activity (Pardossi-Piquard et al. 2009). Thus, TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity (Chen et al. 2006). TMP21 modulates cell growth of papillary thyroid cancer cells by inducing autophagy through activation of the AMPK/mTOR pathway (Xu et al. 2015). TMED2 may regulate inflammation in lung adenocarcinoma (LUAD) through the TLR4/NF-kappaB signaling pathway and enhance the proliferation, development, and prognosis of LUAD by regulating inflammation (Feng et al. 2022).

 

Tmed10 of Homo sapiens

 
9.B.188.1.5

Transmembrane emp24 domain-containing protein, eclair or Eca, of 216 aas and 2 TMSs, N- and C-terminal. Eca and Bai are essential, though not redundant, for dorsoventral patterning of the embryo. They are required during early embryogenesis for the activity of maternal Tkv receptor (TC# 8.B.23.1.27), while the zygotic Tkv is not affected (Bartoszewski et al. 2004). It may also be involved in Golgi organization (Kondylis et al. 2011). Ecla and Bai are involved in the early secretory pathway of Wingless/Wnt, but only Bai interacts with wingless (Wg) (Li et al. 2015).

EMP24 of Drosophila melanogaster (Fruit fly)

 
9.B.188.1.6

Transmembrane emp24 domain-containing protein Baiser or Bai, of 206 aas and 2 TMSs, N- and C-terminal. Eca (TC# 9.B.188.1.5) and Bai are essential, though not redundant, for dorsoventral patterning of the embryo (Bartoszewski et al. 2004). They are specifically required during early embryogenesis for the activity of the maternal Kkv receptor, while the zygotic Tkv is not affected. Ecla and Bai are involved in the early secretory pathway of Wingless/Wnt, but only Bai interacts with wingless (Wg) (Li et al. 2015).

Bai of Drosophila melanogaster

 
9.B.188.1.7

p24 protein (EMP24-1; GP25) of 210 aas and 2 TMSs, N- and C-terminal. It is a cargo receptor involved in ER to golgi vesticle transport (Carney and Bowen 2004). The p24/transmembrane emp24 domain (TMED) family of cargo receptors has been shown to be important in development and disease (Aber et al. 2019).

p24 of Drosophila melanogaster (Fruit fly)

 
9.B.188.1.8

Transmembrane emp24 domain-containing protein 7, TMED7, of 224 aas and 2 TMSs, N- and C-terminal. It plays a role in vesicular protein trafficking, mainly in the early secretory pathway. It appears to function in the biosynthesis of secreted cargo including processing and post-translational modifications and thereby in embyogenesis (Nie et al. 2020).

TMED7 of Homo sapiens