TMEM273

Transmembrane protein 273 (TMEM273) aka C10orf128, is a protein which in humans is encoded by the TMEM273 gene. This protein is found within the topological domain as TMEM273 is a single-pass type I membrane protein.^[5] Although the function TMEM273 is relatively novel within the scientific community, existing research has shown that the protein may mediate histone trimethylation modifications, immunosuppression, and macrophage chemotaxis inhibition.^[6] TMEM273 expression is ubiquitous and is associated with various diseases and illnesses. Recent studies have revealed likely links to lung adenocarcinomas and acute myeloid leukemia^[7][6]

This gene is located on chromosome 10, long arm, region 1, band 1, sub-band 23 (10q11.23), and oriented on the minus strand in Homo sapiens, and contains 7 exons.^[8] The gene spans 33,656 base pairs. A common alias of TMEM273 is C10orf128. The locus of TMEM273 is denoted by the red line in the figure below.

TMEM273 gene encodes 7 transcript variants. Transcript variant 2 contains an alternate exon in the central coding region, which results in a frameshift, compared to variant 1. However, the encoded isoform 2 has a longer and more distinct C-terminus.^[9] Transcript variant 2 is 1601 nt long, contains 7 exons, and is considered the MANE Select (most representative) variant.

Conceptual translation of the Human TMEM273 isoform 2 protein begins with the 5' UTR and ends with the 3' UTR. Between the untranslated regions lies the coding sequence. The figure is annotated with start and stop codons, exon boundaries, highly conserved regions among distant orthologs, internal repeats, domains of unknown function (DUF regions), signal peptides, transmembrane regions, poly-A sites, and single nucleotide polymorphisms.

TMEM273 isoform 2 contains 129 amino acids and has an approximate molecular weight of 14 kDa with an isoelectric point of 9.5.^[10]

TMEM 273 expression is ubiquitous and variable among tissues. It has the highest expression in the lungs, spleen, and uterus respectively for total RNA in normal tissue.^[11] Expression appears to be lower in the brain, skeletal muscle, liver, and in endocrine glands.^[11] This suggests that TMEM273 is likely not highly involved in the processes of these tissues.

TMEM273 is highly expressed in lung adenocarcinomas, colorectal cancers, and acute myeloid leukemia .^[12][13]

TMEM273 is predominantly localized in the cell membrane, with transmembrane association.^[14] The protein also has nuclear, endoplasmic reticulum, and mitochondrion subcellular localization, but with lower confidence.^[15]

Secondary structure analyses yield that TMEM273 Isoform 2 contains 2 alpha helices and 2 beta sheets, although, these are not in agreement with the predicted tertiary structure via the AlphaFold database.^[16]

TMEM273 contains no disulfide bond linkages.

TMEM273 is predicted to undergo several phosphorylations and myristoylations.^[14]

V-set and transmembrane domain containing 4 (VSTM4), Anthrax toxin receptor-like (ANTXRL), and Arf-GAP with GTPase (AGAP6) are experimentally verified via SNP array to interact with TMEM273.^[17] VSTM4 localizes to the extracellular region and plasma membrane of cells, which is consistent with the localization of TMEM273.^[18] VSTM4 is involved in endothelial cell proliferation, retina blood vessel maintenance, and vasculature development.^[19] ANTXRL also localizes to the plasma membrane and is involved in metal ion binding.^[20] AGAP6 localizes to the cytosol and nucleus and enables GTPase activator activity.^[21]

The TMEM gene family is very large and consists of integral membrane proteins serving vastly different functions. In addition to their wide variety of functions, TMEM proteins are expressed in many different organ types, and their mediation in physiological processes makes them attractive proteins to study disease etiology. TMEM273 first appeared approximately 462 million years ago in Chondrichthyes (cartilaginous fish). NCBI pBLAST^[22] yielded 2 splice isoforms of TMEM273 in the sevengill sharpnose shark, one of the most distantly related orthologs.

TMEM273 exhibits a higher evolutionary rate than cytochrome c. This is consistent with patterns seen in other rapidly evolving proteins such as fibrinogen alpha.

Investigation of p53 mutation-based prognostic risk signatures for acute myeloid leukemia (AML) found TMEM273 to be a potential prognostic biomarker for patients with AML.^[23] Although this data is not fully extrapolated, an additional study into FMS-like tyrosine kinase 3 (FLT3) found TMEM273 to be expressed in FLT3-mutated AML.^[24] FLT3 is essential to hematopoiesis, and mutations in this gene are commonly seen in AML.^[25] Therefore it is possible that TMEM273's link to AML is a result of its mediation of FLT3.

In a study targeting Ebola-associated genes within the human genome, TMEM273 was found to be a signal peptide expressed in blood plasma, indicating that the protein may play a role in controlling protein secretion and trafficking.^[26] Another study investigating surrogate biomarkers for protective immunity against Chlamydia trachomatis revealed TMEM273 to be a prerequisite for interleukin-13 (IL-13) production by CD4 clones, suggesting the protein to be a T-Cell biomarker.^[27] Specifically, TMEM273 was prominent in the CD4 and CD8 signatures of the genital tract. The implication that TMEM273 is a T-Cell biomarker could potentially illuminate why the protein is, prevalent in many different types of malignant tissue.

An investigation into the prognosis of patients with lung adenocarcinoma (LUAD) found that poor prognosis was consistently related to histone hypotrimethylation level, decreased secretion of chemokines, macrophage chemotaxis inhibition, and immunosuppression; A TMEM-based signature was found to be closely related to these prognoses.^[6] The TMEM signature includes TMEM273, TMEM125 and TMEM163.^[6] The involvement of these proteins in mediating histone trimethylation modifications, immunosuppression, and macrophage chemotaxis inhibition is likely the cause of this result.^[6]