TMED5

Gene

General properties

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]

Expression

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]

View of human TMED5 gene isoform 1 and 2 with promoter and exon locations.
Conceptual translation of TMED5. Labeled are the start and stop codon, exon splice sites, domains and motifs, polyadenylation signals, predicted RNA and miRNA binding proteins, and predicted post-translational modifications. Bolded amino acids and nucleotides represent highly conserved amongst distant orthologs.

mRNA transcript

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]

Protein

General properties

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]

Composition

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]

Domains and motifs
TMED5 protein isoform 1 visual made via Protter.[15]
TMED5 protein isoform 2 visual made via Protter.[15]

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]

Structure

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]

Predicted tertiary structure of TMED5 generated by Phyre2.[20] Signal peptide is highlighted in yellow. GOLD domain in the lumen is shown to be made up of beta sheets. Transmembrane domain is grayed out followed by the short cytosolic sequence.

Post-translational modifications

TMED5 has two predicted phosphorylation sites in the cytosolic region, Ser227 and Thr229.[21][22]

Localization

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]

Interacting proteins

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

Function and clinical significance

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]

Evolution

Paralogs

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 evolutionary graph shows evolutionary rate. Cytochrome C is shown to represent a slow-evolutionary rate and Fibrinogen alpha represents a fast-evolutionary rate. TMED5 is shown to have a fast-evolutionary rate similar to Fibrinogen alpha. Estimated date of divergence for paralogs were plotted: TMED1 diverged ~64 million years ago (MYA), TMED3 diverged ~118 MYA, and TMED7 diverged ~122 MYA.

Orthologs

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]
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

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