Transmembrane and Tetratricopeptide repeat containing 4 is a protein that in humans is encoded by the TMTC4 gene. This protein crosses the plasma membrane 10 times, and resides in the ER lumen and cytosol. The predicted structure of the TMTC4 protein is a series of alpha-helices.
Gene
TMTC4 is located on chromosome 13 at 13q32.3. The gene is flanked by ADP ribosylation factor 4 pseudogene 3 (ARF4P3) on the left, and ribosomal protein S26 pseudogene 47 (RPS26P47) on the right. TMTC4 spans 4043 bp and has a total of 23 exons.
mRNA
TMTC4 has seven isoform variants, the most common being isoform 1 at 4043 bp. Isoform Length (bp)14043238333350044217541206403773827 The 5’ UTR for TMTC4 is short and in many of the shorter isoforms, portions of this untranslated region are cut. In comparison, the 3’ UTR is long and is often complete across the seven isoforms.
Protein
Physical properties
The molecular weight for TMTC4 is 85.0 kdal, and there are no positive, negative, or neutral clusters of amino acids or charge runs exceeding the normal lengths. When looking at a distant ortholog (purple sea urchin) the molecular weight of TMTC4 is 85.5 kdal and there, again, are no charge runs, positive, negative or neutral clusters, or unusual spacings. There are strong similarities in protein composition across species. The isoelectric point for the domain of unknown function (DUF 1736) is lower than that of the protein overall.
Domain Amino Acids Molecular Weight (kdal) Isoelectric PointHuman TMTC476085.09.135DUF 1736758.64.123TPR repeats23426.79.509
Domains
TMTC4 has ten transmembrane regions, all of them spaced within the first half of the protein.
TMTC4 is layered with tetratricopeptide (TPR) repeat sequences that are a part of the TPR superfamily of proteins. DUF1736 is present upstream of the TPR region. A seven residue repeat (SRR) is located toward the end of the protein, and it is thought to encode a coiled-coil structure. Another member of the TPR family, PFTA (protein prenyltransferases alpha subunit repeat), is located within the protein's TPR region and is believed to be involved in signal transduction and vesicular traffic regulation. LSPR coagulation factor V, also a repeat motif, is located within the TPR region, and is thought to be a central regulator of hemostasis.
Secondary structure
TMTC4 takes on a series of alpha-helix structures, especially within the TPR region, though there are a minimal amount of beta-strand structures spaced throughout the beginning half of the protein.
Post-translational modifications
There are four predicted nuclear localization signals, each tagging the protein for nuclear import. At the very end of the protein, however, there is a predicted ER retention signal which would prevent the protein from leaving the ER. The protein has three predicted N-glycosylation sites, potentially altering its structure and function and there are ten predicted phosphorylation sites, each a possible activation site for a regulatory mechanism.
Expression
TMTC4 is expressed in all human tissues. The gene, however, is most highly expressed in the brain and in the spinal cord.
Protein abundance seems to be lower than normal for TMTC4.
Regulation
There is one possible promoter for the TMTC4 gene, located in the 5’ UTR but before the start of the coding sequence.
Function
Currently the function of TMTC4 has not been characterized.
Interacting proteins
Possible interacting proteins are NRG1, PEX19, HERC3, TXNDC15, and COL1A1 . All of these were detected through affinity chromatography. Protein Name Known function LocationNeuregulin 1 [NRG1]mediates cell to cell signalingmembrane glycoproteinPeroxisomal Biogenesis Factor 19 [PEX19]cytosolic chaperonemembrane receptor proteinECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 3 [HERC3]member of the ubiquitin ligase familycytosolThioredoxin Domain Containing 15 [TXNDC15]Not knownNot knownCollagen Type I Alpha 1 Chain [COL1A1]triple helix collagen proteinextracellular
Homology
Orthologs
Ortholog space for TMTC4 spans a large portion of evolutionary time. TMTC4 is present in mammals, reptiles, amphibians, birds, fish, and invertebrates. It is not present in plants, bacteria, archaea, or fungi. Sequence Number Genus and species Common name Accession # (protein) Identity Date of Divergence (MYA)1Heterocephalus glaberNaked mole ratEHB03258.188%942Rattus norvegicusBrown ratNP_001127886.190%943Myotis brandtiiBrandt's batEPQ01527.190%944Pteropus alectoBlack flying foxXP_006909447.193%885Erinaceus europaeusEuropean hedgehogXP_016040457.185%946Sorex araneusCommon shrewXP_004614101.186%947Sus scrofaWild boarNP_001239134.191%948Lipotes vexilliferBaijiXP_007461591.190%889Ailuropoda melanoleucaGiant pandaXP_019650336.190%9410Acinonyx jubatusCheetahXP_014931490.193%9411Tyto albaBarn owlKFV56414.185%32012Charadrius vociferusKilldeerKGL87053.184%32013Python bivittatusBurmese pythonXP_007425712.181%32014Anolis carolinensisCarolina anoleXP_008105174.182%32015Xenopus tropicalisWestern clawed frogNP_001121486.138%35316Nanorana parkeriNanorana parkeriXP_018432106.173%35317Callorhinchus miliiAustralian ghostsharkXP_007885231.168%46518Crassostrea gigasPacific oysterXP_011422949.150%75819Strongylocentrotus purpuratusPurple sea urchinXP_011670776.149%627
Paralogs
Paralog space for TMTC4 spans the gene family TMTC. There are four genes in this gene family: TMTC1, TMTC2, TMTC3, and TMTC4. TMTC1 and TMTC3 split from TMTC4 about 1200 million years ago, while TMTC2 split from TMTC4 1400 million years ago. Both of these events happened somewhere between invertebrates and plants.
References
Further reading