Transmembrane emp24 domain-containing protein 5 is a protein that in humans is encoded by the TMED5 gene.National Center for Biotechnology Information. "Transmembrane p24 trafficking protein 5". NCBI Gene.
Gene
General properties TMED5 (transmembrane emp24 domain-containing protein 5) 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.Weizmann Institute of Science. "TMED5 Gene". Gene Cards Human Gene Database.
Expression TMED5 has ubiquitous expression with transcripts detected in 246 tissues.UniProt Consortium. "TMED5 gene". UniProtKB. Androgen deprivation led to lower expression in mice splenocytes compared to the control.National Center for Biotechnology Information (NCBI). "GDS5301 Expression Profile". Gene Expression Omnibus Repository. Human dendritic cells infected with Chlamydia pneumoniae showed an absence of TMED5 expression compared to uninfected dendritic cells which had moderate expression.National Center for Biotechnology Information (NCBI). "GDS3573 Expression Profile". Gene Expression Omnibus Repository.
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.Center of Biological Sequential Analysis. "SignalP-5.0 Server". Prediction Servers. After cleavage of the signal peptide, TMED5 isoform 1 is composed of 202 amino acids and has a molecular weight of ~23 kDa.National Center for Biotechnology Information. "Transmembrane emp24 domain-containing protein 5 isoform 1 precursor". NCBI Protein. The mature form of isoform 2 is composed of 166 amino acids and has a molecular weight of ~19 kDa.National Center for Biotechnology Information. "Transmembrane emp24 domain-containing protein 5 isoform 2 precursor". NCBI Protein. Both isoforms have an isolectric point of approximately 4.6.Swiss Institute of Bioinformatics. "Compute pI/Mw Tool". ExPASy.
Composition Compared to the reference set of human proteins, TMED5 has fewer alanine and proline residues but more aspartic acid and phenylalanine residues.European Molecular Biology Laboratory - European Bioinformatics Institute (EMBL-EBI). "Statistical Analysis of Protein Sequences (SAPS)". 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 (helical) 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.The Eukaryotic Liner Motif (ELM) resource for Functional Sites in Proteins. "ELM prediction".Prediction of Protein Sorting Signals and Localization Sites in Amino Acid Sequences. "PSORT II Prediction". PSORT WWW Server.
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.Max Planck Institute (MPI) for Developmental Biology, Tübingen, Germany. "Ali2D". MPI Bioinformatics Toolkit.University of Michigan. "I-TASSER Protein Structure & Function Predictions". Zhang Lab.
Post-translational modifications TMED5 has two predicted phosphorylation sites in the cytosolic region, Ser227 and Thr229.Swiss Institute of Bioinformatics. "MyHits Motif Scan" . ExPASy.Blom, Nikolaj. "Net Phos 3.1 Server". DTU Bioinformatics.
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.Tissue Atlas. "Tissue expression of TMED5". The Human Protein Atlas.
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 IDTransmembrane emp24 domain-containing protein 2TMED2IntActHomo sapiensAnti tag coimmunoprecipitationAssociation28514442Transmembrane emp24 domain-containing protein 10TMED10IntActMus musculusAnti tag coimmunoprecipitationAssociation26496610Protein ERGIC-53LMAN1MINTHomo sapiensFluorescence microscopyColocalization22094269C-X-C motif chemokine 9CXCL9IntActHomo sapiensValidated two hybridPhysical Association32296183Protein arginine N-methyltransferase 6PRMT6MINTHomo sapiensTwo hybridPhysical Association23455924Phosphatidylethanolamine-binding protein 1PEBP1IntActHomo sapiensAnti tag coimmunoprecipitationAssociation31980649Kinase suppressor of Ras 1KSR1IntActHomo sapiensAnti tag coimmunoprecipitationAssociation27086506Endothelial lipaseLIPGIntActMus musculusAnti tag coimmunoprecipitationAssociation28514442Histone-lysine N-methyltransferase PRDM16Prdm16MINTMus musculusAnti tag coimmunoprecipitationAssociation30462309Intracellular growth locus, subunit CiglC2MINTFrancisella tularensisTwo hybrid pooling approachPhysical Association26714771ORF9CORF9CBioGRIDSARS-Cov-2Affinity Capture-MSAssociation32353859Uncharacterized protein 14ORF14IntActSARS-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 (GPI-AP) depend on p24 cargo receptors for transport from the ER to the Golgi. 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.
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.National Center for Biotechnology Information. "Standard Protein BLAST". 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 (MYA)Temple University Center of Biodiversity. "Pairwise Divergence Time". Timetree: The Timescale of Life.Sequence lengthSequence identityHomo sapiens (Human)NP_057124.30229100Pan troglodytes (Chimpanzee)XP_001154650.1622999.6Mus musculus (Mouse)NP_083152.18922990Monodelphis domestica (Gray short-tailed opossum) XP_016284519.116022884Gallus gallus (Chicken)NP_001007957.131822683Gekko japonicus (Gekko)XP_015268825.131824573.1Xenopus tropicalis (Western clawed frog)XP_031755940.135122367.7Danio rerio (Zebrafish)NP_956697.143322565.1Rhincodon typus (Whale shark)XP_020385910.146522466.8Octopus vulgaris (Octopus)XP_029646555.173623942.5Cryptotermes secundus (Termite)XP_023712535.173623537.5Caenorhabditis elegans (Roundworm)NP_502288.173623437.3Drosophila mojavensis (Fruit fly)XP_002009472.273623936.3Eufriesea mexicana (Orchid bee)XP_017762298.173622726.8Trichoplax adhaerensXP_002108774.174719332.1Rhizopus microsporus XP_023464765.1101719930.2Coprinopsis cinerea (Gray shag mushroom)XP_001836898.2101719928.5Kluyveromyces lactisXP_453709.1101720828.1Rhodamnia argentea (Malletwood)XP_030545696.1127521728.9Quercus suber (Cork oak)XP_023882547.1127527728.7Vitis riparia (Riverbank grape)XP_034686416.1127521527.3
References