TMED5

TMED5
Identifiers
AliasesTMED5, CGI-100, p28, p24g2, transmembrane p24 trafficking protein 5
External IDsOMIM: 616876; MGI: 1921586; HomoloGene: 4996; GeneCards: TMED5; OMA:TMED5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

50999

73130

Ensembl

ENSG00000117500

ENSMUSG00000063406

UniProt

Q9Y3A6

Q9CXE7

RefSeq (mRNA)

NM_001167830
NM_016040

NM_028876
NM_001347383
NM_001361466
NM_001361467

RefSeq (protein)

NP_001161302
NP_057124

NP_001334312
NP_083152
NP_001348395
NP_001348396

Location (UCSC)Chr 1: 93.15 – 93.18 MbChr 5: 108.25 – 108.28 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Transmembrane emp24 domain-containing protein 5 is a protein that in humans is encoded by the TMED5 gene.[5]

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]

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 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]

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[25] Association 28514442
Histone-lysine N-methyltransferase PRDM16 Prdm16 MINT Mus musculus Anti tag coimmunoprecipitation[32] Association 30462309
Intracellular growth locus, subunit C iglC2 MINT Francisella tularensis Two hybrid pooling approach[33] Physical Association 26714771
ORF9C ORF9C BioGRID SARS-Cov-2 Affinity Capture-MS[34] Association 32353859
Uncharacterized protein 14 ORF14 IntAct SARS-Cov-2 Pull down[34] 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.[35] TMED5 is thought to be necessary in the formation of the Golgi into a ribbon.[36]

Glycosylphosphatidylinositol-anchored proteins (GPI-AP) depend on p24 cargo receptors for transport from the ER to the Golgi.[37] 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.[37]

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.[38] 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.[39]

Research has identified bladder cancer to have a common chromosomal amplification at 1p21-22 and showed significant upregulation of TMED5.[40]

Evolution

Homology

Paralogs

TMED5 paralogs include TMED1, TMED2, TMED3, TMED4, TMED6, TMED7, TMED8, TMED9, and TMED10.[41] 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]

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)[42] Sequence Length Sequence Identity[41]
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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