TM6SF2

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.National Center for Biotechnology Information, U.S. National Library of Medicine website https://www.ncbi.nlm.nih.gov/

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.National Center for Biotechnology Information, U.S. National Library of Medicine website. AceView program.https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/ The microRNA miR-1343 binds to a 3’ UTR site called 7mer-m8 (as predicted by TargetScan{{cite journal | vauthors = Agarwal V, Bell GW, Nam JW, Bartel DP | title = Predicting effective microRNA target sites in mammalian mRNAs | journal = eLife | volume = 4 | pages = e05005 | date = August 2015 | pmid = 26267216 | pmc = 4532895 | doi = 10.7554/eLife.05005 | doi-access = free }}).

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.mfold web server: 1995-2014, Michael Zuker & Nick Markham, © Rensselaer Polytechnic Institute. Hosted by The RNA Institute, College of Arts and Sciences, State University of New York at Albany.http://mfold.rna.albany.edu/?q=mfold/RNA-Folding-Form

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/PAX5Genomatix Gene2Promoter program. http://www.genomatix.de/ {{Webarchive|url=https://web.archive.org/web/20211202010908/https://www.genomatix.de/ |date=2021-12-02 }} and two SNP regions have been identified as well.National Center for Biotechnology Information, U.S. National Library of Medicine website. SNP:GeneView program.https://www.ncbi.nlm.nih.gov/SNP/ 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.San Diego Super Computer (SDSC) Biology Workbench online program. SAPS protein assessment program.http://workbench.sdsc.edu/

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.{{cite journal | vauthors = Petersen TN, Brunak S, von Heijne G, Nielsen H | title = SignalP 4.0: discriminating signal peptides from transmembrane regions | journal = Nature Methods | volume = 8 | issue = 10 | pages = 785–6 | date = September 2011 | pmid = 21959131 | doi = 10.1038/nmeth.1701 | s2cid = 16509924 | doi-access = free }}

File:Conceptual TM6SF2 protein with phosphorylation sites.png

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.San Diego Super Computer (SDSC) Biology Workbench online program. CHOFAS program.

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.DISULFIND program:

Ceroni, A. Passerini, A. Vullo and P. Frasconi. DISULFIND: a Disulfide Bonding State and Cysteine Connectivity Prediction Server, Nucleic Acids Research, 34(Web Server issue):W177--W181, 2006.http://disulfind.dsi.unifi.it/

Two main post-translational modifications occur; phosphorylation at tyrosine, serine and tryptophan sites and two low probability sumoylation sites.ExPASy Bioinformatics Resource Portal. Proteomics tool. http://expasy.org/proteomics

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.National Center for Biotechnology Information, U.S. National Library of Medicine website. GEO Profiles.https://www.ncbi.nlm.nih.gov/geoprofiles

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.{{cite journal | vauthors = Mahdessian H, Taxiarchis A, Popov S, Silveira A, Franco-Cereceda A, Hamsten A, Eriksson P, van't Hooft F | title = TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 24 | pages = 8913–8 | date = June 2014 | pmid = 24927523 | pmc = 4066487 | doi = 10.1073/pnas.1323785111 | bibcode = 2014PNAS..111.8913M | doi-access = free }}

No known protein-protein interactions have been established thus far.MINT program {{cite web |url=http://mint.bio.uniroma2.it/mint/Welcome.do |title=MINT database |accessdate=2011-05-09 |url-status=dead |archiveurl=https://web.archive.org/web/20060506110418/http://mint.bio.uniroma2.it/mint/Welcome.do |archivedate=2006-05-06 }}IntAct program http://www.ebi.ac.uk/intact/STRING program http://string.embl.de/

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.US patent office. Predictors of transplant rejection determined by peripheral blood gene-expression profiling. Publication number; US8053182 B2. Publication type; Grant. Application number; US 10/587,569. PCT number; PCT/US2005/002697. Publication date; Nov 8, 2011. Inventors; Thomas Cappola, Jonathan A. Epstein.

A variant TM6SF2 gene causes susceptibility to nonalcoholic fatty liver disease due to impaired very low density lipoprotein (VLDL) production.{{cite journal | vauthors = Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, Vogt TF, Hobbs HH, Cohen JC | title = Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease | journal = Nature Genetics | volume = 46 | issue = 4 | pages = 352–6 | date = April 2014 | pmid = 24531328 | doi = 10.1038/ng.2901 | pmc=3969786}}

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.

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