TMEM74B

File:3D structure data for human TMEM74B.png

Predicted 3D structural model of human TMEM74B. Configured using the iCn3D structural viewer, the model displays a characteristic multi-pass topology consisting of 2 transmembrane alpha-helices. Residues are color-coded individually by amino acid identity.

Transmembrane protein 74B (TMEM74B) which is also known as C20orf46 is a protein which in humans is encoded by the TMEM74B gene. TMEM74B is involved in protein binding and is localized to the plasma membrane.

Gene

Location & Gene Neighborhood

The human TMEM74B gene is on chromosome 20 (20p13). It is located on the minus strand, spanning approximately 8,849 base pairs. It is flanked upstream by the RAD21L1 (Rad21 Cohesion Complex Component Like 1), which encodes a nuclear cohesion complex protein critical for chromosome pairing, sister chromatid cohesion, and DNA repair during meiosis. Downstream, it is flanked by the PSMF1 (Proteasome Inhibitor Subunit 1) which encodes a structural regulator that binds and inhibits the 20s proteasome complex to modulate intracellular protein degradation and turnover.

Expression

Normal physiological conditions

A multiple dataset analysis of the 3 RNA-sequence data sets from the gene database record at NCBI for human TMEM74B, microarray NCBI GEO profiles GDS3113, GDS3834, and GDS1096 across all tissues, and in situ hybridization data, indicates that under normal physiological conditions human TMEM74B is expressed at overall low to moderate levels and is tissue specific. The highest expressed tissues overall were the small intestine and duodenum within the gastrointestinal tract, fetal and developing tissues in the central nervous system, and at specific somatic barrier tissues such as the lungs and placenta.

Abnormal physiological conditions

Analyzation of microarray NCBI GEO profiles of abnormal physiological conditions; high and low chromosomal instability phenotypes in stage 2 and 3 colorectal cancers, type 2 diabetes pancreatic beta cells, and human herpes virus infection of primary pulmonary microvascular cells indicated that under abnormal and unstable physiological conditions such as viral stress, metabolic disease, or high chromosomal instability TMEM74B is expressed at higher levels.

Transcript & Protein

Transcript Properties

Human TMEM74B has 17 transcript variants that encode 7 protein isoforms. 9 of these transcript variants are human reviewed alternative variants that all together encode 2 protein isoforms. The other 8 transcript variants which were identified by computational modeling and await manual curation encode 5 protein isoforms. The primary referenced transcript is variant 2 (NM_001304748.2) which has a length of 1876 nucleotides, contains 3 exons and encodes isoform 1 (NP_001291677.1).

File:TMEM74B Transcript Variants & Encoding Proteins.png

Human TMEM74B transcript variants and encoding protein isoforms. Amino acid length, nucleotide length, isoform accession numbers, and transcript accession numbers.

Protein Properties, Subcellular Localization, & Structure

The primary referenced protein isoform of human TMEM74B, isoform 1, is encoded by transcript variant 2 and is composed of 256 amino acids and has an approximate molecular weight of 27.6 kDa. The calculated isoelectric point (pI) for the complete sequence is 6.97. This neutral score is atypical for a human transmembrane protein, which tend to skew basic with isoelectric points in the 8.5-9.5 range. Statistical Analysis of Protein Sequences (SAPS) demonstrated that this global neutrality is maintained by highly polarized, offsetting, structural microdomains. The protein has a highly polarized structure with a neutral global scale that is a result of basic regulatory cluster balancing out the heavily acidic disordered loops and slightly acidic transmembrane cores.

Amino acid sequence analysis of human TMEM74B on PSORT and DeepLoc 2.0 indicated that the subcellular localization shares an equal distribution probability between the endoplasmic reticulum, plasma membrane, and lysosome. The tools predicted the presence of both a signal peptide and 2 highly hydrophobic transmembrane segments. Secondary structure analysis via JPred confirmed the presence of 2 tightly packed parallel transmembrane alpha helices .

Homology

Paralogs

There is a single paralog for human TMEM74B which is human TMEM74 shown below. There is a 45% identity and 57% similarity between the two. The main function of its paralog is to regulate and induce autophagy.

File:Paralog Table of Human TMEM74B.png

Table of Paralog of TMEM74B in Humans, TMEM74B. The annotations on this table were obtained from the NCBI Nucleotide and NCBI Protein records for human TMEM74B.

Orthologs

The human TMEM74B gene possesses hundreds of documented orthologs distributed widely across vertebrate lineages, including diverse classes of mammals, birds, amphibians, and fish. As shown in the table below, TMEM74B is overall moderately to highly conserved across species even in the instance of 429 MYA of divergence.

File:Ortholog Table of human TMEM74B.png

Table of Orthologs of TMEM74B in Humans. Sorted first by estimated date of divergence, then by sequence identity to human protein. Color coordinated by species type. The annotations on this table were obtained from the NCBI Nucleotide and NCBI Protein records for human TMEM74B.

Phylogeny

Below is a phylogenetic tree showing the evolutionary history of TMEM74B and its orthologs. The evolutionary divergence times for these species span from approximately 87 million years ago for closely related mammalian lineages to 429 MYA for basal fish lineages.

File:Phylogenetic Tree of TMEM74B.png

Phylogenetic tree of human TMEM74B across various mammalian, amphibian, bird, and fish species.

Clinical significance

Genomic and expression profiling links variations and dysregulation of the TMEM74B locus to four distinct pathological conditions spanning developmental, hematological, psychiatric, and ophthalmic phenotypes. It is associated with;

• Twin-To-Twin Transfusion Syndrome; a complication of monochorionic twin pregnancies that arise from unbalanced placental vascular anastomoses that result in unidirectional shunting of blood from 1 twin to the other
• Neonatal Anemia; an anemia in newborns characterized by an abnormally low red blood cell count for neonates
• Body Dysmorphic Disorder ; a somatoform mental disorder with pervasive and intrusive beliefs about one's perceived defects or flaws in appearance that results in severe emotional distress and impairment in functioning.
• Achromatopsia; a retinal disorder that results from absence/severe dysfunction of cone photoreceptors, producing marked impairment of color vision and central visual function.

References

This article "TMEM74B" is from Wikipedia. The list of its authors can be seen in its historical and/or the page Edithistory:TMEM74B. Articles copied from Draft Namespace on Wikipedia could be seen on the Draft Namespace of Wikipedia and not main one.

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