TM6SF2 is located on chromosome 19 precisely at locus 19p13.3-p12. It is flanked by SUGP1 (a SURP and G-Patch Domain-Containing protein thought to play a role in pre-mRNA splicing ) and HAPLN4 (a hyaluronan and proteoglycan link protein 4 that binds to hyaluronic acid and may be involved in formation of the extracellular matrix ) genes upstream and downstream respectively.
TM6SF2 is a moderately conserved gene. There exist orthologs in several phyla as far diverged as invertebrates. 82 organisms have been identified as having orthologs of this gene. The most distant orthologs of TM6SF2 are in zebra fish (Danio rerio) and the deer tick (Ixodes scapularis). Below is a summary table of some of the gene orthologs obtained from the NCBI database.
TM6SF1 has been identified as a paralog of TM6SF2 in humans about which little is known.
The domain of unknown function DUF2781 is highly conserved across homologs. DUF2781 belongs to the pfam10914 family which comprises uncharacterized eukaryotic proteins, some of which are membrane proteins
The RNA product is 1483 base pairs long and is spliced alternatively to yield seven different isoforms (alternative mRNAs a - f with form a being the most abundant) with varying combinations of the 10 identified exons. The microRNA miR-1343 binds to a 3’ UTR site called 7mer-m8 (as predicted by TargetScan).
The 5' and 3' UTR regions of the mRNA show some stem loop formation for stability. Much of this chemistry appears to be taking place in the 5' region which has three stem loops compared to the 3' region with only one.
There are ten different exons and the ones expressed depend on how alternative splicing proceeds. There are four alternative polyadenylation sites present.
The promoter for this gene is upstream and spans bases 19383923 to 19384700 (778 bp long) on the minus strand of chromosome 19. There exist several transcription factors capable of binding to this promoter region including cAMP responsive element binding protein, SMAD3, KLF3, EGR1, SOX/SRY, PAX2/PAX5 and two SNP regions have been identified as well. The transcription factors predicted to bind the TM6SF2 promoter suggest this protein functions in growth and tumor regulation as well as sex determination to a lesser extent.
The TM6SF2 protein contains 377 amino acids and is 42,554 Da large with an isoelectric point of about 7.7.
There is a domain of unknown function, DUF2781 ( pfam10914 family) spanning amino acids 218 to 359 in the C-terminus of the protein. There are nine transmembrane regions in this protein. The first one contains the signal peptide which is eventually cleaved following protein localization to the ER. A terminal KHHQ sequence is an endoplasmic reticulum retention signal.
Several alpha helices and beta strands are formed by the mature protein with as many as thirteen helices (including transmembrane helices) and fifteen beta sheets predicted.
The protein side groups in this protein do not necessarily interact in a manner to form tertiary and quaternary structures. The cysteines present are not predicted to form stable disulfide bonds.
Two main post-translational modifications occur; phosphorylation at tyrosine, serine and tryptophan sites and two low probability sumoylation sites.
In humans, TM6SF2 expression has been documented in the adult stage only specifically in the intestine and liver in moderate amounts as well as embryonic tissue and ovary at low levels. Other sources indicate expression in brain, lung, testis, stomach, heart, colon, kidney and adipose tissue.
Protein subcellular localization studies with confocal microscopy demonstrated that TM6SF2 is localized in the endoplasmic reticulum and the ER-Golgi intermediate compartment of human liver cells.
No known protein-protein interactions have been established thus far.
In a study that used pre-made kits to predict cardiac allograft rejection using peripheral blood only, graft rejection was associated with decreased levels of TM6SF2 expression, alongside other genes.
A variant TM6SF2 gene causes susceptibility to nonalcoholic fatty liver disease due to impaired very low density lipoprotein (VLDL) production14.
TM6SF2 inhibition was associated with reduced secretion of TG-rich lipoproteins (TRLs) and increased cellular TG concentration and lipid droplet content, whereas TM6SF2 overexpression reduced liver cell steatosis. TM6SF2 is a regulator of liver fat metabolism with opposing effects on the secretion of TRLs and hepatic lipid droplet content.