| MFSD6L | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | MFSD6L , major facilitator superfamily domain containing 6 like | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | MGI: 2384904 HomoloGene: 17128 GeneCards: MFSD6L | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Major facilitator superfamily domain containing 6 like (MFSD6L) is a protein encoded by the MFSD6L gene in humans. [5] The MFSD6L protein is a transmembrane protein that is part of the major facilitator superfamily (MFS) that uses chemiosmotic gradients to facilitate the transport of small solutes across cell membranes.
In the human genome, the MFSD6L gene is located on chromosome 17 (17p13.1). [5] The DNA sequence encoding the polypeptide encompasses 2,256 bases, starting from 8,797,110 bp to 8,799,365 bp. [6] Additionally, the gene sequence resides on the minus strand. [5] The MFSD6L gene has one alias called FLJ35773. [5]
The encoding DNA sequence results in only one exon in the translated mRNA sequence. [6]
The tumor suppressor gene TP53 was also found within the gene neighborhood of MFSD6L at 17p13.1. [7]
The MFSD6L gene was not found to have other isoforms due to the presence of only one exon in the MFSD6L encoding sequence.
The MFSD6L protein has a precursor molecular weight of approximately 64 kDa, consisting of 586 amino acids. [5] After post-translational modifications, such as glycosylation, the mature MFSD6L protein's molecular weight increases to 72 kDa. Of the amino acids consisting the MFSD6L protein, leucine was found to have increased levels compared to most other human proteins. This increase in leucine is also present in the MFSD6L protein of the house mouse and chimpanzee. [8] The protein also has an isoelectric point of 8.87 pI. [9]
The peptide sequence contains 11 transmembrane regions that cross the plasma membrane. Additionally, there are also two MFS regions starting at the 28th and 368th encoding amino acids. [10]
For the secondary structure of the MFSD6L protein, there are 16 predicted alpha helices and 3 predicted beta sheets. [11] The large amount of alpha helices within the structure of MFSD6L can be attributed to the protein being a transmembrane solute transporter since alpha helices are usually the part of the protein's structure that is positioned within the cell membrane.
Within the tertiary structure, there was a disulfide bond predicted between the two cysteines at the 29th and 311th amino acids. [12]
There was only one promoter region, spanning 1,107 bp, found for MFSD6L using the Genomatix Gene2Promoter database. [13] For the part of the promoter region closest to the start of the 5' UTR of the MFSD6L gene, there were several transcription factor binding sites found. A transcription factor binding site of note was the site for the p53 tumor suppressor protein. [13]
The MFSD6L gene was found to be highly expressed in the pancreas, salivary glands, and the thyroid. [14]
Inspection of in-situ hybridization expression of MFSD6L gene shows that the gene is particularly expressed within glandular cells within their respective tissues.
Expression of the MFSD6L was found to be upregulated as a result of glucose starvation. [15]
Since there is only one exon and no introns within the MFSD6L gene, There is no splicing performed on the MFSD6L mRNA. [10] Translation of the MFSD6L protein initiates at the end of the 5' UTR, which is the first 245 nucleotides of the MFSD6L mRNA. There are conserved stem-loop regions across mammalian orthologs, which infer possible miRNA binding sites.
The subcellular localization of the MFSD6L protein is predicted to be within the cell membrane via DeepLoc tool. [16] This is supported by it being a solute symporter similar to MFS proteins. The first 28 amino acids of the translated MFSD6L protein contains the signal peptide. [17]
Additionally, n-glycosylation sites were predicted at the 110th, 129th, and 224th amino acids of the protein sequence. [16] A serine phosphorylation site at the 429th amino acid was also predicted and verified by presence within other mammalian orthologs. [18]
The MFSD6 protein was found to be the only paralog to the human MFSD6L protein. [5]
Through BLAST sequence analysis, the MFSD6L protein was found to have orthologs in a many mammalian species, especially among primates, and flying foxes. [19] There were some orthologs found in the Reptilia and Amphibia classes, albeit not as great in number as in the Mammalia. Among fish, there were significantly more orthologs found amongst ray-finned fishes than cartilaginous fishes. Additionally, the jaw-less fish, the sea lamprey, was also found to be an ortholog.
There were also multiple orthologs found amongst invertebrates, such as echinoderms and mollusks.
No significant orthologs of the MFSD6L protein were found amongst insects; however there were orthologs found in the bacteria. Specifically, the Anaerolinea genus, which contains thermophilic bacteria were found to have orthologs with the human protein due to its regions of MFS being identical to MFS regions found in the human protein. The following table shows some examples of orthologs of the human MFSD6L.
| Genus and Species | Common Name | Taxonomic Group | Median Time since Divergence (MYA) | Accession Number (from NCBI) | Sequence Length (aa) | Sequence Identity (%) | Sequence Similarity (%) |
| Homo sapiens | Human | Primates | 0 | NP_689812.3 | 586 | 100% | 100% |
| Mus musculus | House Mouse | Rodentia | 89 | NP_666116.1 | 586 | 68% | 77% |
| Monodon monoceros | Narwhal | Artiodactyla | 94 | XP_029068193.1 | 595 | 73% | 81% |
| Molossus molossus | Velvety Free-tailed Bat | Chiroptera | 94 | XP_036125248.1 | 600 | 72% | 79% |
| Dermochelys coriacea | Leatherback Sea Turtle | Testudines | 318 | XP_038228264.1 | 653 | 45% | 59% |
| Terrapene carolina triunguis | Three-toed Box Turtle | Testudines | 318 | XP_024071382.1 | 654 | 44% | 57% |
| Patagioenas fasciata monilis | Band-tailed Pigeon | Columbiformes | 318 | OPJ90083.1 | 655 | 43% | 55% |
| Dromaius novaehollandiae | Emu | Casuariiformes | 318 | XP_025976398.1 | 628 | 42% | 55% |
| Microcaecilia unicolor | Tiny Cayenne Caecilian | Gymnophiona | 351.7 | XP_030063970.1 | 652 | 44% | 58% |
| Xenopus tropicalis | Western-clawed Frog | Anura | 351.7 | XP_002937042.2 | 611 | 42% | 56% |
| Bufo bufo | Common Toad | Anura | 351.7 | XP_040293432.1 | 615 | 39% | 54% |
| Scleropages formosus | Asian Arowana | Osteoglossiformes | 433 | NP_001003586.1 | 585 | 40% | 55% |
| Danio rerio | Zebrafish | Cypriniformes | 433 | XP_018612492.2 | 542 | 33% | 49% |
| Callorhinchus milii | Australian Ghostfish | Chimaeriformes | 465 | XP_042198386.1 | 630 | 41% | 57% |
| Petromyzon marinus | Sea Lamprey | Petromyzontiformes | 599 | XP_032823230.1 | 735 | 26% | 38% |
| Anneissia japonica | Sea Lily | Comatulida | 627 | XP_033125701.1 | 616 | 28% | 47% |
| Gigantopelta aegis | Deep Sea Snail | Neomphalida | 736 | XP_041362795.1 | 637 | 27% | 46% |
| Crassostrea gigas | Pacific Oyster | Ostreida | 736 | XP_011445242.2 | 615 | 25% | 44% |
| Octopus sinesis | East Asian Common Octopus | Octopoda | 736 | XP_029655326 | 634 | 24% | 43% |
| Tetranychus urticae | Red Spider Mite | Trombidiformes | 736 | XP_015795313.1 | 872 | 14% | 25% |
| Anaerolinealis | Anaerolinealis bacterium | Anaerolineales | 4090 | MBN1451601.1 | 389 | 19% | 34% |
The main homologous domains found within the MFSD6L protein are the MFS regions. Since MFS includes a large amount of solute transporter proteins within its superfamily, there are many MFS proteins that have the same homologous MFS domains.
Through BLAST sequence analysis, the most distant homologs were the organisms within the Cnidaria phylum, which mainly consists of jellyfish, sea anemones, and corals. [19] Searching with BLAST for the MFSD6L gene at an older diverging phylum, the Porifera, revealed no homologous MFSD6L protein.
As a result of the MFSD6L protein's presence in Cnidaria and absence in Porifera, the estimated emergence date of the MFSD6L gene lies between 687 and 777 MYA, which are the divergence dates found from TimeTree. [20] From the corrected % divergence chart and calculations of the corrected % divergence of the Homo sapiens MFSD6 paralog, the estimated date of emergence of the MFSD6L protein was found to be around 736 MYA.
The MFSD6L protein was not found to have any experimentally-verified protein-protein interactions. [21]
The polypeptide sequence contains many transmembrane regions, identifying the MFSD6L protein as a transmembrane protein for transporting solutes across the plasma membrane of a cell. Tertiary structure prediction tools suggest that the structure of the MFSD6L protein is similar to 1PV6A, a β-galactosides symporter which uses proton gradients to transport solutes. [22] [23] As a result, the function of the MFSD6L protein could possibly a sugar symporter. This is additionally supported by the fact that the expression of MFSD6L was upregulated due to glucose starvation.
A disease associated with the MFSD6L gene is the Tetralogy of Fallot, which is a series of four congenital heart defects that can cause low oxygenation of blood. [5] This is due to a ventricular septal defect that causes the mixing of oxygenated and deoxygenated blood in the left ventricle of the heart.
The MFSD6L gene was also found to be a candidate gene taking part in the disease Pediatric Cataract. [24]
Various SNP's were found within the encoding sequence of the MFSD6L protein sequence as shown below.
| Amino Acid Position | mRNA Position | Original Nucleotide | SNP | Original Amino Acid | Variant Amino Acid | Codon |
| 328 | 1212 | T | T | Ser [S] | Leu [L] | 2 |
| 399 | 1424 | G | A | Gly [G] | Ser [S] | 1 |
| 406 | 1446 | C | T | Ser [S] | Leu [L] | 2 |
| 571 | 1941 | C | T | Thr [T] | Ile [I] | 2 |
| 574 | 1949 | G | A | Asp [D] | Asn [N] | 1 |
| 575 | 1952 | T | G | Trp [W] | Gly [G] | 1 |
The solute carrier (SLC) group of membrane transport proteins include over 400 members organized into 66 families. Most members of the SLC group are located in the cell membrane. The SLC gene nomenclature system was originally proposed by the HUGO Gene Nomenclature Committee (HGNC) and is the basis for the official HGNC names of the genes that encode these transporters. A more general transmembrane transporter classification can be found in TCDB database.
The major facilitator superfamily (MFS) is a superfamily of membrane transport proteins that facilitate movement of small solutes across cell membranes in response to chemiosmotic gradients.
Protein FAM214A, also known as protein family with sequence similarity 214, A (FAM214A) is a protein that, in humans, is encoded by the FAM214A gene. FAM214A is a gene with unknown function found at the q21.2-q21.3 locus on Chromosome 15 (human). The protein product of this gene has two conserved domains, one of unknown function (DUF4210) and another one called Chromosome_Seg. Although the function of the FAM214A protein is uncharacterized, both DUF4210 and Chromosome_Seg have been predicted to play a role in chromosome segregation during meiosis.
Transmembrane protein 33 is a protein that in humans, is encoded by the TMEM33 gene, also known as SHINC3. Another name for the TMEM33 protein is DB83.
Solute carrier family 46 member 3 (SLC46A3) is a protein that in humans is encoded by the SLC46A3 gene. Also referred to as FKSG16, the protein belongs to the major facilitator superfamily (MFS) and SLC46A family. Most commonly found in the plasma membrane and endoplasmic reticulum (ER), SLC46A3 is a multi-pass membrane protein with 11 α-helical transmembrane domains. It is mainly involved in the transport of small molecules across the membrane through the substrate translocation pores featured in the MFS domain. The protein is associated with breast and prostate cancer, hepatocellular carcinoma (HCC), papilloma, glioma, obesity, and SARS-CoV. Based on the differential expression of SLC46A3 in antibody-drug conjugate (ADC)-resistant cells and certain cancer cells, current research is focused on the potential of SLC46A3 as a prognostic biomarker and therapeutic target for cancer. While protein abundance is relatively low in humans, high expression has been detected particularly in the liver, small intestine, and kidney.
Coiled-coil domain 47 (CCDC47) is a gene located on human chromosome 17, specifically locus 17q23.3 which encodes for the protein CCDC47. The gene has several aliases including GK001 and MSTP041. The protein itself contains coiled-coil domains, the SEEEED superfamily, a domain of unknown function (DUF1682) and a transmembrane domain. The function of the protein is unknown, but it has been proposed that CCDC47 is involved in calcium ion homeostasis and the endoplasmic reticulum overload response.
TMEM143 is a protein that in humans is encoded by TMEM143 gene. TMEM143, a dual-pass protein, is predicted to reside in the mitochondria and high expression has been found in both human skeletal muscle and the heart. Interaction with other proteins indicate that TMEM143 could potentially play a role in tumor suppression/expression and cancer regulation.
Transmembrane protein 251, also known as C14orf109 or UPF0694, is a protein that in humans is encoded by the TMEM251 gene. One notable feature of this protein is the presence of proline residues on one of its predicted transmembrane domains., which is a determinant of the intramitochondrial sorting of inner membrane proteins.
Chromosome 9 open reading frame 152 is a protein that in humans is encoded by the C9orf152 gene. The exact function of the protein is not completely understood.
TMEM249 is a protein that in humans is encoded by the C8orfk29 gene.
Atypical Solute Carrier Families are novel plausible secondary active or facilitative transporter proteins that share ancestral background with the known solute carrier families (SLCs). However, they have not been assigned a name according to the SLC root system, or been classified into any of the existing SLC families.
TMEM44 is a protein that in humans is encoded by the TMEM44 gene. DKFZp686O18124 is a synonym of TMEM44.
LOC101928193 is a protein which in humans is encoded by the LOC101928193 gene. There are no known aliases for this gene or protein. Similar copies of this gene, called orthologs, are known to exist in several different species across mammals, amphibians, fish, mollusks, cnidarians, fungi, and bacteria. The human LOC101928193 gene is located on the long (q) arm of chromosome 9 with a cytogenic location at 9q34.2. The molecular location of the gene is from base pair 133,189,767 to base pair 133,192,979 on chromosome 9 for an mRNA length of 3213 nucleotides. The gene and protein are not yet well understood by the scientific community, but there is data on its genetic makeup and expression. The LOC101928193 protein is targeted for the cytoplasm and has the highest level of expression in the thyroid, ovary, skin, and testes in humans.
Single-pass membrane and coiled-coil domain-containing protein 3 is a protein that is encoded in humans by the SMCO3 gene.
Leucine rich single-pass membrane protein 2 is a single-pass membrane protein rich in leucine, that in humans is encoded by the LSMEM2 gene. The LSMEM2 protein is conserved in mammals, birds, and reptiles. In humans, LSMEM2 is found to be highly expressed in the heart, skeletal muscle and tongue.
Transmembrane protein 247 is a multi-pass transmembrane protein of unknown function found in Homo sapiens encoded by the TMEM247 gene. Notable in the protein are two transmembrane regions near the c-terminus of the translated polypeptide. Transmembrane protein 247 has been found to be expressed almost entirely in the testes.
TMEM275 is a protein that in humans is encoded by the TMEM275 gene. TMEM275 has two, highly-conserved, helical trans-membrane regions. It is predicted to reside within the plasma membrane or the endoplasmic reticulum's membrane.
SMIM19, also known as Small Integral Membrane Protein 19, encodes the SMIM19 protein. SMIM19 is a confirmed single-pass transmembrane protein passing from outside to inside, 5' to 3' respectively. SMIM19 has ubiquitously high to medium expression with among varied tissues or organs. The validated function of SMIM19 remains under review because of on sub-cellular localization uncertainty. However, all linked proteins research to interact with SMIM19 are associated with the endoplasmic reticulum (ER), presuming SMIM19 ER association
Transmembrane protein 101 (TMEM101) is a protein that in humans is encoded by the TMEM101 gene. The TMEM101 protein has been demonstrated to activate the NF-κB signaling pathway. High levels of expression of TMEM101 have been linked to breast cancer.
Transmembrane protein 212 is a protein that in humans is encoded by the TMEM212 gene. The protein consists of 5 transmembrane domains and localizes in the plasma membrane and endoplasmic reticulum. TMEM212 has orthologs in vertebrates but not invertebrates.TMEM212 has been associated with sporadic Parkinson's disease, facial processing, and adiposity in African Americans.
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