Transmembrane emp24 domain-containing protein 5 is a protein that in humans is encoded by the TMED5 gene.[1]

Gene

General properties

TMED5 (transmembrane emp24 domain-containing protein 5) is also known as p28, p24g2, and CGI-100.[1] 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.[2]

Expression

TMED5 has ubiquitous expression with transcripts detected in 246 tissues.[3] Androgen deprivation led to lower expression in mice splenocytes compared to the control.[4] Human dendritic cells infected with Chlamydia pneumoniae showed an absence of TMED5 expression compared to uninfected dendritic cells which had moderate expression.[5]

mRNA transcript

TMED5 has two coding transcript variants and one non-coding transcript variant produced by alternative splicing.[3] 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.[1]

Protein

General properties

TMED5 contains a signal peptide.[6] After cleavage of the signal peptide, TMED5 isoform 1 is composed of 202 amino acids and has a molecular weight of ~23 kDa.[7] The mature form of isoform 2 is composed of 166 amino acids and has a molecular weight of ~19 kDa.[8] Both isoforms have an isolectric point of approximately 4.6.[9]

Composition

Compared to the reference set of human proteins, TMED5 has fewer alanine and proline residues but more aspartic acid and phenylalanine residues.[10] TMED5 isoform 1 has one hydrophobic segment that corresponds with its transmembrane region.[10]

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.[3]

TMED5 is part of the emp24/gp25L/p24 family/GOLD family protein.[3]

TMED5 contains a di-lysine motif and predicted NLS in its cytoplasmic tail.[11][12]

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.[13][14]

Post-translational modifications

TMED5 has two predicted phosphorylation sites in the cytosolic region, Ser227 and Thr229.[15][16]

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.[12][17]

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.[18]

Protein NameProtein AbrevDB SourceSpeciesEvidenceInteractionPubMed ID
Transmembrane emp24 domain-containing protein 2TMED2IntActHomo sapiensAnti tag coimmunoprecipitation[19]Association28514442
Transmembrane emp24 domain-containing protein 10TMED10IntActMus musculusAnti tag coimmunoprecipitation[20]Association26496610
Protein ERGIC-53LMAN1MINTHomo sapiensFluorescence microscopy[21]Colocalization22094269
C-X-C motif chemokine 9CXCL9IntActHomo sapiensValidated two hybrid[22]Physical Association32296183
Protein arginine N-methyltransferase 6PRMT6MINTHomo sapiensTwo hybrid[23]Physical Association23455924
Phosphatidylethanolamine-binding protein 1PEBP1IntActHomo sapiensAnti tag coimmunoprecipitation[24]Association31980649
Kinase suppressor of Ras 1KSR1IntActHomo sapiensAnti tag coimmunoprecipitation[25]Association27086506
Endothelial lipaseLIPGIntActMus musculusAnti tag coimmunoprecipitation[19]Association28514442
Histone-lysine N-methyltransferase PRDM16Prdm16MINTMus musculusAnti tag coimmunoprecipitation[26]Association30462309
Intracellular growth locus, subunit CiglC2MINTFrancisella tularensisTwo hybrid pooling approach[27]Physical Association26714771
ORF9CORF9CBioGRIDSARS-Cov-2Affinity Capture-MS[28]Association32353859
Uncharacterized protein 14ORF14IntActSARS-Cov-2Pull down[28]Association32353859

Function and clinical significance

TMED5 is a part of the p24 protein family whose general functions are protein trafficking for the secretory pathway.[29] TMED5 is thought to be necessary in the formation of the Golgi into a ribbon.[30]

Glycosylphosphatidylinositol-anchored proteins (GPI-AP) depend on p24 cargo receptors for transport from the ER to the Golgi.[31] 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.[31]

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.[32] 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.[33]

Research has identified bladder cancer to have a common chromosomal amplification at 1p21-22 and showed significant upregulation of TMED5.[34]

Evolution

Homology

Paralogs

TMED5 paralogs include TMED1, TMED2, TMED3, TMED4, TMED6, TMED7, TMED8, TMED9, and TMED10.[35] All paralogs share the conserved transmembrane domain and contain the characteristic GOLD domain as included in the emp24/gp25L/p24 family/GOLD family proteins.[3]

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.[1] The following table provides a sample of the ortholog space of TMED5.

Genus and speciesNCBI Accession NumberDate of Divergence (MYA)[36]Sequence lengthSequence identity[35]
Homo sapiens (Human)NP_057124.30229100
Pan troglodytes (Chimpanzee)XP_001154650.1622999.6
Mus musculus (Mouse)NP_083152.18922990
Monodelphis domestica (Gray short-tailed opossum)XP_016284519.116022884
Gallus gallus (Chicken)NP_001007957.131822683
Gekko japonicus (Gekko)XP_015268825.131824573.1
Xenopus tropicalis (Western clawed frog)XP_031755940.135122367.7
Danio rerio (Zebrafish)NP_956697.143322565.1
Rhincodon typus (Whale shark)XP_020385910.146522466.8
Octopus vulgaris (Octopus)XP_029646555.173623942.5
Cryptotermes secundus (Termite)XP_023712535.173623537.5
Caenorhabditis elegans (Roundworm)NP_502288.173623437.3
Drosophila mojavensis (Fruit fly)XP_002009472.273623936.3
Eufriesea mexicana (Orchid bee)XP_017762298.173622726.8
Trichoplax adhaerensXP_002108774.174719332.1
Rhizopus microsporusXP_023464765.1101719930.2
Coprinopsis cinerea (Gray shag mushroom)XP_001836898.2101719928.5
Kluyveromyces lactisXP_453709.1101720828.1
Rhodamnia argentea (Malletwood)XP_030545696.1127521728.9
Quercus suber (Cork oak)XP_023882547.1127527728.7
Vitis riparia (Riverbank grape)XP_034686416.1127521527.3

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