TM6SF2 is the Transmembrane 6 superfamily 2 human gene which codes for a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

by the same name. This gene is otherwise called KIAA1926.GeneCards® The Human Database Compendium website https://www.genecards.org/ Its exact function is currently unknown.

Location

TM6SF2 is located on

chromosome 19 Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. It is considered the most gene-rich chromosome ...

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/

Evolutionary aspects

Orthologs

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 Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

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.

Paralogs

TM6SF1 has been identified as a

paralog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

of TM6SF2 in humans about which little is known.

Homologous domains

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

mRNA

The RNA product is 1483 base pairs long and is spliced alternatively to yield seven different

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

(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 In bioinformatics, TargetScan is a web server that predicts biological targets of microRNAs (miRNAs) by searching for the presence of sites that match the seed region of each miRNA. For many species, other types of sites, known as 3'-compensatory ...

Folding patterns

The 5' and 3' UTR regions of the mRNA show some

stem loop Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence whe ...

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.

Exons and introns

There are ten different

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

and the ones expressed depend on how alternative splicing proceeds. There are four alternative

polyadenylation Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euk ...

sites present.

Promoter region

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 In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...

capable of binding to this promoter region including

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

responsive element binding protein,

SMAD3 Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene. SMAD3 is a member of the SMAD family of proteins. It acts as a mediator of the signals initiated by t ...

KLF3 Krüppel-like factor 3 is a protein that in humans is encoded by the ''KLF3'' gene. Structure KLF3, originally termed Basic Krüppel-like Factor (BKLF), was the third member of the Krüppel-like factor family of zinc finger transcription fact ...

EGR1 EGR-1 (Early growth response protein 1) also known as ZNF268 (zinc finger protein 268) or NGFI-A (nerve growth factor-induced protein A) is a protein that in humans is encoded by the ''EGR1'' gene. EGR-1 is a mammalian transcription factor. It wa ...

SOX Sox most often refers to: * Boston Red Sox, an MLB team * Chicago White Sox, an MLB team * An alternate spelling of socks Sox may also refer to: Places * SOX, Sogamoso Airport's IATA airport code, an airport in Colombia Computing and technolo ...

/ SRY,

PAX2 Paired box gene 2, also known as Pax-2, is a protein which in humans is encoded by the ''PAX2'' gene. Function The Pax Genes, or Paired-Box Containing Genes, play important roles in the development and proliferation of multiple cell lines, dev ...

PAX5 Paired box protein Pax-5 is a protein that in humans is encoded by the ''PAX5'' gene. Function The PAX5 gene is a member of the paired box (PAX) family of transcription factors. The central feature of this gene family is a novel, highly cons ...

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.

Protein

The TM6SF2 protein contains 377 amino acids and is 42,554 Da large with an isoelectric point of about 7.7.

Domains and motifs

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 A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

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. Conceptual TM6SF2 protein with phosphorylation sites

Conceptual TM6SF2 protein with phosphorylation sites

Secondary structure

Several

alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

and beta strands are formed by the mature protein with as many as thirteen helices (including transmembrane helices) and fifteen

beta sheets The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

predicted.

3° and 4° structure

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 In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

Post-translational modifications

Two main post-translational modifications occur;

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

at tyrosine, serine and tryptophan sites and two low probability sumoylation sites.

Expression patterns

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.

Protein interactions

No known protein-protein interactions have been established thus far.

Clinical significance

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 Variant may refer to: In arts and entertainment * ''Variant'' (magazine), a former British cultural magazine * Variant cover, an issue of comic books with varying cover art * ''Variant'' (novel), a novel by Robison Wells * " The Variant", 2021 e ...

TM6SF2 gene causes susceptibility to

nonalcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic f ...

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.

References

{{Reflist, 33em