TMED5


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

Gene

General properties

TMED5 is also known as p28, p24g2, and CGI-100. 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.

Expression

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

mRNA transcript

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

Protein

General properties

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

Composition

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

Domains and motifs

TMED5 isoform 1 is a single-pass transmembrane protein and is composed of a lumenal domain, one transmembrane domain, and a cytoplasmic domain.
TMED5 is part of the emp24/gp25L/p24 family/GOLD family protein.
TMED5 contains a di-lysine motif and predicted NLS in its cytoplasmic tail.

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.

Post-translational modifications

TMED5 has two predicted phosphorylation sites in the cytosolic region, Ser227 and Thr229.

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.

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.
Protein NameProtein AbrevDB SourceSpeciesEvidenceInteractionPubMed ID
TMED2Homo sapiensAnti tag coimmunoprecipitationAssociation28514442
TMED10Mus musculusAnti tag coimmunoprecipitationAssociation26496610
LMAN1Homo sapiensFluorescence microscopyColocalization22094269
CXCL9Homo sapiensValidated two hybridPhysical Association32296183
PRMT6Homo sapiensTwo hybridPhysical Association23455924
PEBP1Homo sapiensAnti tag coimmunoprecipitationAssociation31980649
KSR1Homo sapiensAnti tag coimmunoprecipitationAssociation27086506
LIPGMus musculusAnti tag coimmunoprecipitationAssociation28514442
Prdm16Mus musculusAnti tag coimmunoprecipitationAssociation30462309
iglC2Francisella tularensisTwo hybrid pooling approachPhysical Association26714771
ORF9CORF9CSARS-Cov-2Affinity Capture-MSAssociation32353859
ORF14SARS-Cov-2Pull downAssociation32353859

Function and clinical significance

TMED5 is a part of the p24 protein family whose general functions are protein trafficking for the secretory pathway. TMED5 is thought to be necessary in the formation of the Golgi into a ribbon.
Glycosylphosphatidylinositol-anchored proteins depend on p24 cargo receptors for transport from the ER to the Golgi. Knockdown of 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.
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. 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.
Research has identified bladder cancer to have a common chromosomal amplification at 1p21-22 and showed significant upregulation of ''TMED5.''

Evolution

Homology

Paralogs

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

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. The following table provides a sample of the ortholog space of TMED5.
Genus and speciesNCBI Accession NumberDate of Divergence Sequence lengthSequence identity
Homo sapiens 0229100
Pan troglodytes 622999.6
Mus musculus 8922990
Monodelphis domestica 16022884
Gallus gallus 31822683
Gekko japonicus 31824573.1
Xenopus tropicalis 35122367.7
Danio rerio 43322565.1
Rhincodon typus 46522466.8
Octopus vulgaris 73623942.5
Cryptotermes secundus 73623537.5
Caenorhabditis elegans 73623437.3
Drosophila mojavensis 73623936.3
Eufriesea mexicana 73622726.8
Trichoplax adhaerens74719332.1
Rhizopus microsporus101719930.2
Coprinopsis cinerea 101719928.5
Kluyveromyces lactis101720828.1
Rhodamnia argentea 127521728.9
Quercus suber 127527728.7
Vitis riparia 127521527.3