TMED5 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | TMED5, CGI-100, p28, p24g2, transmembrane p24 trafficking protein 5 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 616876 MGI: 1921586 HomoloGene: 4996 GeneCards: TMED5 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Transmembrane emp24 domain-containing protein 5 is a protein that in humans is encoded by the TMED5 gene.[5]
TMED5 (transmembrane emp24 domain-containing protein 5) is also known as p28, p24g2, and CGI-100.[5] The human gene spans 30,775 base pairs over 4 exons and 3 introns for transcript variant 1, 5 exons and 4 introns for transcript variant 2, and it is located on the minus strand of chromosome 1, at 1p22.1.[6]
TMED5 has ubiquitous expression with transcripts detected in 246 tissues.[7] Androgen deprivation led to lower expression in mice splenocytes compared to the control.[8] Human dendritic cells infected with Chlamydia pneumoniae showed an absence of TMED5 expression compared to uninfected dendritic cells which had moderate expression.[9]
TMED5 has two coding transcript variants and one non-coding transcript variant produced by alternative splicing.[7] Isoform 1 has 4 exons and encodes a protein 229 amino acids. Isoform 2 has 5 exons and encodes a protein with a shorter C-terminus 193 amino acids due to an additional exon causing a frameshift.[5]
TMED5 contains a signal peptide.[10] After cleavage of the signal peptide, TMED5 isoform 1 is composed of 202 amino acids and has a molecular weight of ~23 kDa.[11] The mature form of isoform 2 is composed of 166 amino acids and has a molecular weight of ~19 kDa.[12] Both isoforms have an isolectric point of approximately 4.6.[13]
Compared to the reference set of human proteins, TMED5 has fewer alanine and proline residues but more aspartic acid and phenylalanine residues.[14] TMED5 isoform 1 has one hydrophobic segment that corresponds with its transmembrane region.[14]
TMED5 isoform 1 is a single-pass transmembrane protein and is composed of a lumenal domain, one transmembrane (helical) domain, and a cytoplasmic domain.[7]
TMED5 is part of the emp24/gp25L/p24 family/GOLD family protein.[7]
TMED5 contains a di-lysine motif and predicted NLS in its cytoplasmic tail.[16][17]
The structure of TMED5 isoform 1 consists of beta strands making up the lumenal region, disparate coil-coiled regions, alpha helices making up the transmembrane domain, and alpha helices making up some of the cytoplasmic domain.[18][19]
TMED5 has two predicted phosphorylation sites in the cytosolic region, Ser227 and Thr229.[21][22]
TMED5's predicted location is in the plasma membrane, with an extracellular N-terminus and intracellular C-terminus. TMED5's localization is predicted to be cytoplasmic, but has been found in some tissues to be located in the nucleus.[17][23]
The following table provides a list of proteins most likely to interact with TMED5. Not shown in the table are Wnt family proteins which are known to interact with the p24 protein family.[24]
Protein Name | Protein Abrev | DB Source | Species | Evidence | Interaction | PubMed ID |
---|---|---|---|---|---|---|
Transmembrane emp24 domain-containing protein 2 | TMED2 | IntAct | Homo sapiens | Anti tag coimmunoprecipitation[25] | Association | 28514442 |
Transmembrane emp24 domain-containing protein 10 | TMED10 | IntAct | Mus musculus | Anti tag coimmunoprecipitation[26] | Association | 26496610 |
Protein ERGIC-53 | LMAN1 | MINT | Homo sapiens | Fluorescence microscopy[27] | Colocalization | 22094269 |
C-X-C motif chemokine 9 | CXCL9 | IntAct | Homo sapiens | Validated two hybrid[28] | Physical Association | 32296183 |
Protein arginine N-methyltransferase 6 | PRMT6 | MINT | Homo sapiens | Two hybrid[29] | Physical Association | 23455924 |
Phosphatidylethanolamine-binding protein 1 | PEBP1 | IntAct | Homo sapiens | Anti tag coimmunoprecipitation[30] | Association | 31980649 |
Kinase suppressor of Ras 1 | KSR1 | IntAct | Homo sapiens | Anti tag coimmunoprecipitation[31] | Association | 27086506 |
Endothelial lipase | LIPG | IntAct | Mus musculus | Anti tag coimmunoprecipitation[32] | Association | 28514442 |
Histone-lysine N-methyltransferase PRDM16 | Prdm16 | MINT | Mus musculus | Anti tag coimmunoprecipitation[33] | Association | 30462309 |
Intracellular growth locus, subunit C | iglC2 | MINT | Francisella tularensis | Two hybrid pooling approach[34] | Physical Association | 26714771 |
ORF9C | ORF9C | BioGRID | SARS-Cov-2 | Affinity Capture-MS[35] | Association | 32353859 |
Uncharacterized protein 14 | ORF14 | IntAct | SARS-Cov-2 | Pull down[35] | Association | 32353859 |
TMED5 is a part of the p24 protein family whose general functions are protein trafficking for the secretory pathway.[36] TMED5 is thought to be necessary in the formation of the Golgi into a ribbon.[37]
Glycosylphosphatidylinositol-anchored proteins (GPI-AP) depend on p24 cargo receptors for transport from the ER to the Golgi.[38] Knockdown of p24γ2 (a mouse ortholog of TMED5) in mice resulted in impaired transport of GPI-AP. The study concluded that the α-helical region of p24γ2 binds GPI which is necessary to incorporate it into COPII transport vesicles.[38]
TMED5 is reported to be necessary for the secretion of Wnt ligands. TMED5 has been found to interact with WNT7B, activating the canonical WNT-CTNNB1/β-catenin signaling pathway.[39] This pathway is linked to numerous cancers because upregulation of the Wnt/β-catenin signaling pathway leads to cytosolic accumulation of β-catenin, promoting cellular proliferation.[40]
Research has identified bladder cancer to have a common chromosomal amplification at 1p21-22 and showed significant upregulation of TMED5.[41]
TMED5 paralogs include TMED1, TMED2, TMED3, TMED4, TMED6, TMED7, TMED8, TMED9, and TMED10.[42] All paralogs share the conserved transmembrane domain and contain the characteristic GOLD domain as included in the emp24/gp25L/p24 family/GOLD family proteins.[7]
TMED5 is found to be conserved in vertebrates, invertebrates, plants and fungi, and there are 243 known organisms that have orthologs with the gene.[5] The following table provides a sample of the ortholog space of TMED5.
Genus and Species | NCBI Accession Number | Date of Divergence (MYA)[43] | Sequence Length | Sequence Identity[42] |
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Homo sapiens (Human) | NP_057124.3 | 0 | 229 | 100 |
Pan troglodytes (Chimpanzee) | XP_001154650.1 | 6 | 229 | 99.6 |
Mus musculus (Mouse) | NP_083152.1 | 89 | 229 | 90 |
Monodelphis domestica (Gray short-tailed opossum) | XP_016284519.1 | 160 | 228 | 84 |
Gallus gallus (Chicken) | NP_001007957.1 | 318 | 226 | 83 |
Gekko japonicus (Gekko) | XP_015268825.1 | 318 | 245 | 73.1 |
Xenopus tropicalis (Western clawed frog) | XP_031755940.1 | 351 | 223 | 67.7 |
Danio rerio (Zebrafish) | NP_956697.1 | 433 | 225 | 65.1 |
Rhincodon typus (Whale shark) | XP_020385910.1 | 465 | 224 | 66.8 |
Octopus vulgaris (Octopus) | XP_029646555.1 | 736 | 239 | 42.5 |
Cryptotermes secundus (Termite) | XP_023712535.1 | 736 | 235 | 37.5 |
Caenorhabditis elegans (Roundworm) | NP_502288.1 | 736 | 234 | 37.3 |
Drosophila mojavensis (Fruit fly) | XP_002009472.2 | 736 | 239 | 36.3 |
Eufriesea mexicana (Orchid bee) | XP_017762298.1 | 736 | 227 | 26.8 |
Trichoplax adhaerens | XP_002108774.1 | 747 | 193 | 32.1 |
Rhizopus microsporus | XP_023464765.1 | 1017 | 199 | 30.2 |
Coprinopsis cinerea (Gray shag mushroom) | XP_001836898.2 | 1017 | 199 | 28.5 |
Kluyveromyces lactis | XP_453709.1 | 1017 | 208 | 28.1 |
Rhodamnia argentea (Malletwood) | XP_030545696.1 | 1275 | 217 | 28.9 |
Quercus suber (Cork oak) | XP_023882547.1 | 1275 | 277 | 28.7 |
Vitis riparia (Riverbank grape) | XP_034686416.1 | 1275 | 215 | 27.3 |