:TMED5

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. [https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMED5&keywords=tmed5 "TMED5 Gene"]. Gene Cards Human Gene Database.

TMED5 has ubiquitous expression with transcripts detected in 246 tissues.UniProt Consortium. [https://www.uniprot.org/uniprot/Q9Y3A6 "TMED5 gene"]. UniProtKB. Androgen deprivation led to lower expression in mice splenocytes compared to the control.National Center for Biotechnology Information (NCBI). [https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS5301:1424573_PM_at "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). [https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS3573:1558813_at "GDS3573 Expression Profile"]. Gene Expression Omnibus Repository.

File:TMED5 promoter location schematic new.png

File:TMED5 conceptual translation.pdf, 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.]]

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.

TMED5 contains a signal peptide.Center of Biological Sequential Analysis. [http://www.cbs.dtu.dk/services/SignalP/ "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. [https://www.ncbi.nlm.nih.gov/protein/NP_057124.3 "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. [https://www.ncbi.nlm.nih.gov/protein/NP_001161302.1 "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. [https://web.expasy.org/compute_pi/ "Compute pI/Mw Tool"]. ExPASy.

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). [https://www.ebi.ac.uk/Tools/seqstats/saps/ "Statistical Analysis of Protein Sequences (SAPS)"]. TMED5 isoform 1 has one hydrophobic segment that corresponds with its transmembrane region.

File:TMED5 protein visual made via Protter.pngFile:Protter TMED5 isoform 2 visual.png

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. [http://elm.eu.org/ "ELM prediction"]. Prediction of Protein Sorting Signals and Localization Sites in Amino Acid Sequences. [https://psort.hgc.jp/form2.html "PSORT II Prediction"]. PSORT WWW Server.

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. [https://toolkit.tuebingen.mpg.de/tools/ali2d "Ali2D"]. MPI Bioinformatics Toolkit. University of Michigan. [https://zhanglab.ccmb.med.umich.edu/I-TASSER/ "I-TASSER Protein Structure & Function Predictions"]. Zhang Lab.File:Predicted tertiary structure of TMED5 generated by Phyre2.png

TMED5 has two predicted phosphorylation sites in the cytosolic region, Ser227 and Thr229.Swiss Institute of Bioinformatics. [https://myhits.sib.swiss/cgi-bin/motif_scan "MyHits Motif Scan"]. ExPASy. Blom, Nikolaj. [http://www.cbs.dtu.dk/services/NetPhos/ "Net Phos 3.1 Server"]. DTU Bioinformatics.

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. [https://www.proteinatlas.org/ENSG00000117500-TMED5 "Tissue expression of TMED5"]. The Human Protein Atlas.

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.Buechling, T., Chaudhary, V., Spirohn, K., Weiss, M. and Boutros, M. (2011), p24 proteins are required for secretion of Wnt ligands. EMBO reports, 12: 1265-1272. {{doi|10.1038/embor.2011.212}}

TMED5 is a part of the p24 protein family whose general functions are protein trafficking for the secretory pathway.Pastor-Cantizano, N., Montesinos, J.C., Bernat-Silvestre, C. et al. p24 family proteins: key players in the regulation of trafficking along the secretory pathway. Protoplasma 253, 967–985 (2016).{{doi|10.1007/s00709-015-0858-6}} TMED5 is thought to be necessary in the formation of the Golgi into a ribbon.Koegler, E., Bonnon, C., Waldmeier, L., Mitrovic, S., Halbeisen, R. and Hauri, H.‐P. (2010), p28, A Novel ERGIC/cis Golgi Protein, Required for Golgi Ribbon Formation. Traffic, 11: 70-89. {{doi|10.1111/j.1600-0854.2009.01009.x}}

Glycosylphosphatidylinositol-anchored proteins (GPI-AP) depend on p24 cargo receptors for transport from the ER to the Golgi.Theiler, R., Fujita, M., Nagae, M., Yamaguchi, Y., Maeda, Y., & Kinoshita, T. (2014). The α-helical region in p24γ2 subunit of p24 protein cargo receptor is pivotal for the recognition and transport of glycosylphosphatidylinositol-anchored proteins. The Journal of biological chemistry, 289(24), 16835–16843. {{doi|10.1074/jbc.M114.568311}} Knockdown of [https://www.ncbi.nlm.nih.gov/gene/73130 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.Zhen Yang, Qi Sun, Junfei Guo, Shixing Wang, Ge Song, Weiying Liu, Min Liu & Hua Tang (2019) GRSF1-mediated MIR-G-1 promotes malignant behavior and nuclear autophagy by directly upregulating TMED5 and LMNB1 in cervical cancer cells, Autophagy, 15:4, 668-685, {{doi|10.1080/15548627.2018.1539590}} 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.Pai, S.G., Carneiro, B.A., Mota, J.M. et al. Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol 10, 101 (2017). {{doi|10.1186/s13045-017-0471-6}}

Research has identified bladder cancer to have a common chromosomal amplification at 1p21-22 and showed significant upregulation of TMED5.Scaravilli, M., Asero, P., Tammela, T.L. et al. Mapping of the chromosomal amplification 1p21-22 in bladder cancer. BMC Res Notes 7, 547 (2014). {{doi|10.1186/1756-0500-7-547}}

TMED5 paralogs include TMED1, TMED2, TMED3, TMED4, TMED6, TMED7, TMED8, TMED9, and TMED10.National Center for Biotechnology Information. [https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE=Proteins&PROGRAM=blastp&PAGE_TYPE=BlastSearch&BLAST_SPEC= "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.

File:TMED5 Evolutionary graph.png 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. ]]

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.

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Category:Proteins