SLC46A3

The SLC46A3 gene, also known by its aliases solute carrier family 46 member 3 and FKSG16, is located at 13q12.3 on the reverse strand in humans. The gene spans 18,950 bases from 28,700,064 to 28,719,013 (GRCh38/hg38), flanked by POMP upstream and CYP51A1P2 downstream.{{Cite web |title=SLC46A3|url=https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=SLC46A3&submit=Go|website=AceView}} SLC46A3 contains 6 exons and 5 introns. There are two paralogs for this gene, SLC46A1 and SLC46A2, and orthologs as distant as fungi.{{Cite web |title=BLAST: Basic Local Alignment Search Tool|url=https://blast.ncbi.nlm.nih.gov/Blast.cgi|website=NCBI (National Center for Biotechnology Information)}} So far, more than 4580 single nucleotide polymorphisms (SNPs) for this gene have been identified.{{Cite web |title=Variation Viewer (GRCh38)|url=https://www.ncbi.nlm.nih.gov/variation/view/?q=283537%5Bgeneid%5D|website=NCBI (National Center for Biotechnology Information)}} SLC46A3 is expressed at relatively low levels, about 0.5x the average gene.{{Cite web |title=SLC46A3|url=https://pax-db.org/protein/1857285|website=PAXdb}} Gene expression is peculiarly high in the liver, small intestine, and kidney.

SLC46A3 has multiple transcript variants produced by different promoter regions and alternative splicing.{{Cite web|title=SLC46A3|url=https://www.genomatix.de/cgi-bin/eldorado/eldorado.pl?s=1bab282c15399b8df7bc8c1b27f12843;SHOW_ANNOTATION=SLC46A3;ELDORADO_VERSION=E35R1911|website=Genomatix: ElDorado|access-date=2020-08-01|archive-date=2021-08-26|archive-url=https://web.archive.org/web/20210826023924/https://www.genomatix.de/cgi-bin/sessions/login.pl?s=1a35a28b07769763b98450d53a1f4aa8|url-status=dead}} A total of 4 transcript variants are found in the RefSeq database.{{Cite book|last1=Pruitt|first1=Kim |last2=Brown|first2=Garth|last3=Tatusova|first3=Tatiana|last4=Maglott|first4=Donna |author-link4=Donna R. Maglott| name-list-style = vanc |url=https://www.ncbi.nlm.nih.gov/books/NBK21091/|title=The Reference Sequence (RefSeq) Database|date=2012-04-06|publisher=National Center for Biotechnology Information (US)|language=en}} Variant 1 is most abundant.{{Cite journal |title=Homo sapiens solute carrier family 46 member 3 (SLC46A3), transcript variant 1, mRNA|url=https://www.ncbi.nlm.nih.gov/nuccore/NM_181785.4|website=NCBI (National Center for Biotechnology Information) Nucleotide|date=14 December 2020}}

*Lengths shown do not include introns.

3 isoforms have been reported for SLC46A3. Isoform a is MANE select and most abundant.{{Cite web |title=solute carrier family 46 member 3 isoform a precursor [Homo sapiens]|url=https://www.ncbi.nlm.nih.gov/protein/NP_861450.1|website=NCBI (National Center for Biotechnology Information) Protein}} All isoforms contain the MFS and MFS_1 domains as well as the 11 transmembrane regions.{{Cite web |title=solute carrier family 46 member 3 isoform a precursor [Homo sapiens]|url=https://www.ncbi.nlm.nih.gov/protein/NP_001334889.1|website=NCBI (National Center for Biotechnology Information) Protein}}{{Cite web |title=solute carrier family 46 member 3 isoform b precursor [Homo sapiens]|url=https://www.ncbi.nlm.nih.gov/protein/NP_001129391.1|website=NCBI (National Center for Biotechnology Information) Protein}}{{Cite web |title=solute carrier family 46 member 3 isoform X1 [Homo sapiens]|url=https://www.ncbi.nlm.nih.gov/protein/XP_005266418.1|website=NCBI (National Center for Biotechnology Information) Protein}}

*Lengths shown are for the precursor proteins.

SLC46A3 is an integral membrane protein 461 amino acids (aa) of length with a molecular weight (MW) of 51.5 kDa.{{cite journal | vauthors = Brendel V, Bucher P, Nourbakhsh IR, Blaisdell BE, Karlin S | title = Methods and algorithms for statistical analysis of protein sequences | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 6 | pages = 2002–6 | date = March 1992 | pmid = 1549558 | doi = 10.1073/pnas.89.6.2002 | pmc = 48584 | bibcode = 1992PNAS...89.2002B | doi-access = free }} The basal isoelectric point (pI) for this protein is 5.56.{{Citation|last1=Gasteiger|first1=Elisabeth |last2=Hoogland|first2=Christine|last3=Gattiker|first3=Alexandre|last4=Duvaud|first4=S'everine|last5=Wilkins|first5=Marc R.|last6=Appel|first6=Ron D.|last7=Bairoch|first7=Amos | name-list-style = vanc | chapter =Protein Identification and Analysis Tools on the ExPASy Server|date=2005| title =The Proteomics Protocols Handbook|pages=571–607|place=Totowa, NJ|publisher=Humana Press|doi=10.1385/1-59259-890-0:571 |isbn=978-1-58829-343-5}} The protein contains 11 transmembrane domains in addition to domains MFS and MFS_1. MFS and MFS_1 domains largely overlap and contain 42 putative substrate translocation pores that are predicted to bind substrates for transmembrane transport. The substrate translocation pores have access to both sides of the membrane in an alternating fashion through a conformational change. SLC46A3 lacks charged and polar amino acids while containing an excess of nonpolar amino acids, particularly phenylalanine (Phe). The resulting hydrophobicity is mostly concentrated in the transmembrane regions for interactions with the fatty acid chains in the lipid bilayer.{{Cite book |last1=Alberts|first1=Bruce|last2=Johnson|first2=Alexander|last3=Lewis|first3=Julian|last4=Raff|first4=Martin|last5=Roberts|first5=Keith|last6=Walter|first6=Peter | name-list-style = vanc |date=2002| chapter =Membrane Proteins|url=https://www.ncbi.nlm.nih.gov/books/NBK26878/| title =Molecular Biology of the Cell. |publisher=Garland Science | edition = 4th |language=en}} The transmembrane domains also have a shortage of proline (Pro), a helix breaker.

File:SLC46A3_Protein_Sequence_Analysis.png

The protein sequence contains mixed, positive, and negative charge clusters, one of each, which are high in glutamine (Glu). The clusters are located outside the transmembrane regions, and thus are solvent-exposed. Two 0 runs that run through several transmembrane domains in addition to a +/* run in between two transmembrane domains are also present. The protein contains a C-(X)₂-C motif (CLLC), which is mostly present in metal-binding proteins and oxidoreductases.{{cite journal | vauthors = Miseta A, Csutora P | title = Relationship between the occurrence of cysteine in proteins and the complexity of organisms | journal = Molecular Biology and Evolution | volume = 17 | issue = 8 | pages = 1232–9 | date = August 2000 | pmid = 10908643 | doi = 10.1093/oxfordjournals.molbev.a026406 | doi-access = free }} A sorting-signal sequence motif, YXXphi, is also found at Tyr246 - Phe249 (YMLF) and Tyr446 - Leu449 (YELL).{{cite journal | vauthors = Kumar M, Gouw M, Michael S, Sámano-Sánchez H, Pancsa R, Glavina J, Diakogianni A, Valverde JA, Bukirova D, Čalyševa J, Palopoli N, Davey NE, Chemes LB, Gibson TJ | display-authors = 6 | title = ELM-the eukaryotic linear motif resource in 2020 | journal = Nucleic Acids Research | volume = 48 | issue = D1 | pages = D296–D306 | date = January 2020 | pmid = 31680160 | pmc = 7145657 | doi = 10.1093/nar/gkz1030 }}{{Cite web |title=TRG_ENDOCYTIC_2|url=http://elm.eu.org/elms/TRG_ENDOCYTIC_2.html|website=ELM (The Eukaryotic Linear Motif resource for Functional Sites in Proteins)}} This Y-based sorting signal directs the trafficking within the endosomal and the secretory pathways of integral membrane proteins by interacting with the mu subunits of the adaptor protein (AP) complex.{{cite journal | vauthors = Pandey KN | title = Small peptide recognition sequence for intracellular sorting | journal = Current Opinion in Biotechnology | volume = 21 | issue = 5 | pages = 611–20 | date = October 2010 | pmid = 20817434 | doi = 10.1016/j.copbio.2010.08.007 | pmc = 2997389 }} The signal-transducing adaptor protein 1 (STAP1) Src homology 2 (SH2) domain binding motif at Tyr446 - Ile450 (YELLI) is a phosphotyrosine (pTyr) pocket that serves as a docking site for the SH2 domain, which is central to tyrosine kinase signaling.{{Cite web |title=LIG_SH2_STAP1|url=http://elm.eu.org/elms/LIG_SH2_STAP1.html|website=ELM (The Eukaryotic Linear Motif resource for Functional Sites in Proteins)}} Multiple periodicities typical of an α-helix (periods of 3.6 residues in the hydrophobicity) encompass transmembrane domains.{{cite journal | vauthors = Eisenberg D, Weiss RM, Terwilliger TC | title = The hydrophobic moment detects periodicity in protein hydrophobicity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 1 | pages = 140–4 | date = January 1984 | pmid = 6582470 | doi = 10.1073/pnas.81.1.140 | pmc = 344626 | bibcode = 1984PNAS...81..140E | doi-access = free }} 3 tandem repeats with core block lengths of 3 aa (GNYT, VSTF, STFI) are observed throughout the sequence.

File:Helical_Wheel_of_Transmembrane_Domain_3.png

Based on results by Ali2D, the secondary structure of SLC46A3 is rich in α-helices with random coils in between.{{cite journal | vauthors = Zimmermann L, Stephens A, Nam SZ, Rau D, Kübler J, Lozajic M, Gabler F, Söding J, Lupas AN, Alva V | display-authors = 6 | title = A Completely Reimplemented MPI Bioinformatics Toolkit with a New HHpred Server at its Core | journal = Journal of Molecular Biology | volume = 430 | issue = 15 | pages = 2237–2243 | date = July 2018 | pmid = 29258817 | doi = 10.1016/j.jmb.2017.12.007 | s2cid = 22415932 }} More precisely, the protein is predicted to be composed of 62.9% α-helix, 33.8% random coil, and 3.3% extended strand. The regions of α-helices span the majority of the transmembrane domains. The signal peptide is also predicted to form an α-helix, most likely in the h-region.{{cite book |last=Reithmeier|first=Reinhart A.F. | name-list-style = vanc | chapter = Assembly of proteins into membranes|date=1996| title =Biochemistry of Lipids, Lipoproteins and Membranes|series=New Comprehensive Biochemistry |volume=31 |pages=425–471|publisher=Elsevier|doi=10.1016/s0167-7306(08)60523-2 |isbn=978-0-444-82359-5}} The amphipathic α-helices possess a particular orientation with charged/polar and nonpolar residues on opposite sides of the helix mainly due to the hydrophobic effect.{{cite journal | vauthors = Biggin PC, Sansom MS | title = Interactions of alpha-helices with lipid bilayers: a review of simulation studies | journal = Biophysical Chemistry | volume = 76 | issue = 3 | pages = 161–83 | date = February 1999 | pmid = 10074693 | doi = 10.1016/s0301-4622(98)00233-6 }}

File:Membrane_Topology_of_SLC46A3.png

Membrane topology of SLC46A3 shows the 11 α-helical transmembrane domains embedded in the membrane with the N-terminus oriented toward the extracellular region (or lumen of the ER) and the C-terminus extended to the cytoplasmic region.{{cite journal | vauthors = Omasits U, Ahrens CH, Müller S, Wollscheid B | title = Protter: interactive protein feature visualization and integration with experimental proteomic data | journal = Bioinformatics | volume = 30 | issue = 6 | pages = 884–6 | date = March 2014 | pmid = 24162465 | doi = 10.1093/bioinformatics/btt607 | doi-access = free | hdl = 20.500.11850/82692 | hdl-access = free }}{{Cite web |title=Q7Z3Q1 (S46A3_HUMAN)|url=https://www.uniprot.org/uniprot/Q7Z3Q1#Q7Z3Q1-1|website=UniProt}}

File:Tertiary_Structure_of_SLC46A3.png

File:SLC46A3_Ligand_Binding_Sites.png

Model for the tertiary structure of SLC46A3 was constructed by I-TASSER based on a homologous crystal structure of the human organic anion transporter MFSD10 (Tetran) with a TM-score of 0.853.{{cite journal | vauthors = Yang J, Zhang Y | title = I-TASSER server: new development for protein structure and function predictions | journal = Nucleic Acids Research | volume = 43 | issue = W1 | pages = W174-81 | date = July 2015 | pmid = 25883148 | doi = 10.1093/nar/gkv342 | pmc = 4489253 }}{{cite journal | vauthors = Zhang Y, Skolnick J | title = TM-align: a protein structure alignment algorithm based on the TM-score | journal = Nucleic Acids Research | volume = 33 | issue = 7 | pages = 2302–9 | date = 2005-04-11 | pmid = 15849316 | doi = 10.1093/nar/gki524 | pmc = 1084323 }}{{Cite web |title=I-TASSER results|url=https://zhanglab.ccmb.med.umich.edu/I-TASSER/output/S556508/|website=Zhang Lab}} The structure contains a cluster of 17 α-helices that spans the membrane and random coils that connect those α-helices. Multiple ligand binding sites are also predicted to reside in the structure, including those for (2S)-2,3-dihydroxypropyl(7Z)-pentadec-7-enoate (78M), cholesterol hemisuccinate (Y01), and octyl glucose neopentyl glycol (37X).{{cite journal | vauthors = Zhang C, Freddolino PL, Zhang Y | title = COFACTOR: improved protein function prediction by combining structure, sequence and protein-protein interaction information | journal = Nucleic Acids Research | volume = 45 | issue = W1 | pages = W291–W299 | date = July 2017 | pmid = 28472402 | doi = 10.1093/nar/gkx366 | pmc = 5793808 }}{{cite journal | vauthors = Yang J, Roy A, Zhang Y | title = Protein-ligand binding site recognition using complementary binding-specific substructure comparison and sequence profile alignment | journal = Bioinformatics | volume = 29 | issue = 20 | pages = 2588–95 | date = October 2013 | pmid = 23975762 | doi = 10.1093/bioinformatics/btt447 | pmc = 3789548 }}

SLC46A3 carries 4 promoter regions that lead to different transcript variants as identified by ElDorado at Genomatix. Promoter A supports transcript variant 1 (GXT_2836199).

*The coordinates are for GRCh38.

Transcription factors (TFs) bind to the promoter region of SLC46A3 and modulate the transcription of the gene.{{cite book |last=Latchman|first=David S. | name-list-style = vanc | chapter =Methods for Studying Transcription Factors|date=2004|title =Eukaryotic Transcription Factors|journal=The Biochemical Journal |volume=270 |issue=2 |pages=23–53|publisher=Elsevier|doi=10.1016/b978-012437178-1/50008-4 |pmid=2119171 |pmc=1131717 |isbn=978-0-12-437178-1}} The table below shows a curated list of predicted TFs. MYC proto-oncogene (c-Myc), the strongest hit at Genomatix with a matrix similarity of 0.994, dimerizes with myc-associated factor X (MAX) to affect gene expression in a way that increases cell proliferation and cell metabolism.{{Cite web |title=SLC46A3 Transcription Factor Binding Sites|url=https://www.genomatix.de/cgi-bin/matinspector_prof/mat_fam.pl?s=1bab282c15399b8df7bc8c1b27f12843|website=Genomatix: MatInspector}}{{cite journal | vauthors = Miller DM, Thomas SD, Islam A, Muench D, Sedoris K | title = c-Myc and cancer metabolism | journal = Clinical Cancer Research | volume = 18 | issue = 20 | pages = 5546–53 | date = October 2012 | pmid = 23071356 | pmc = 3505847 | doi = 10.1158/1078-0432.CCR-12-0977 }} Its expression is highly amplified in the majority of human cancers, including Burkitt's lymphoma. The heterodimer can repress gene expression by binding to myc-interacting zinc finger protein 1 (MIZ1), which also binds to the promoter of SLC46A3. CCAAT-displacement protein (CDP) and nuclear transcription factor Y (NF-Y) have multiple binding sites within the promoter sequence (3 sites for CDP and 2 sites for NF-Y). CDP, also known as Cux1, is a transcriptional repressor.{{cite journal | vauthors = Ellis T, Gambardella L, Horcher M, Tschanz S, Capol J, Bertram P, Jochum W, Barrandon Y, Busslinger M | display-authors = 6 | title = The transcriptional repressor CDP (Cutl1) is essential for epithelial cell differentiation of the lung and the hair follicle | journal = Genes & Development | volume = 15 | issue = 17 | pages = 2307–19 | date = September 2001 | pmid = 11544187 | pmc = 312776 | doi = 10.1101/gad.200101 }} NF-Y is a heterotrimeric complex of three different subunits (NF-YA, NF-YB, NF-YC) that regulates gene expression, both positively and negatively, by binding to the CCAAT box.{{cite journal | vauthors = Wang GZ, Zhang W, Fang ZT, Zhang W, Yang MJ, Yang GW, Li S, Zhu L, Wang LL, Zhang WS, Liu R, Qian S, Wang JH, Qu XD | s2cid = 6332740 | display-authors = 6 | title = Arsenic trioxide: marked suppression of tumor metastasis potential by inhibiting the transcription factor Twist in vivo and in vitro | journal = Journal of Cancer Research and Clinical Oncology | volume = 140 | issue = 7 | pages = 1125–36 | date = July 2014 | pmid = 24756364 | doi = 10.1007/s00432-014-1659-6 }}

File:NCBI_GEO_profile_of_SLC46a3.png

RNAseq data show SLC46A3 most highly expressed in the liver, small intestine, and kidney and relatively low expression in the brain, skeletal muscle, salivary gland, placenta, and stomach.{{Cite web |title=Illumina bodyMap2 transcriptome|url=https://www.ncbi.nlm.nih.gov/bioproject/PRJEB2445/|website=NCBI (National Center for Biotechnology Information) BioProject}} In fetuses of 10 – 20 weeks, the adrenal gland and intestine report high expression while the heart, kidney, lung, and stomach demonstrate the opposite.{{cite journal | vauthors = Szabo L, Morey R, Palpant NJ, Wang PL, Afari N, Jiang C, Parast MM, Murry CE, Laurent LC, Salzman J | display-authors = 6 | title = Erratum to: Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development | journal = Genome Biology | volume = 17 | issue = 1 | pages = 263 | date = December 2016 | pmid = 27993159 | doi = 10.1186/s13059-016-1123-9 | pmc = 5165717 | doi-access = free }} Microarray data from NCBI GEO present high expression in pancreatic islets, pituitary gland, lymph nodes, peripheral blood, and liver with percentile ranks of 75 or above.{{cite journal | vauthors = Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, Walker JR, Hogenesch JB | display-authors = 6 | title = A gene atlas of the mouse and human protein-encoding transcriptomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 16 | pages = 6062–7 | date = April 2004 | pmid = 15075390 | doi = 10.1073/pnas.0400782101 | pmc = 395923 | bibcode = 2004PNAS..101.6062S | doi-access = free }} Conversely, tissues among the most lowly expressed levels of SLC46A3 include bronchial epithelial cells, caudate nucleus, superior cervical ganglion, smooth muscle, and colorectal adenocarcinoma, all with percentile ranks below 15. Immunohistochemistry supports expression of the gene in the liver and kidney, as well as in skin tissues, while immunoblotting (western blotting) provides evidence for protein abundance in the liver and tonsils, in addition to in papilloma and glioma cells.

File:In_Situ_Hybridization_-_Mouse_Spine_-_SLC46A3.png

In situ hybridization data show ubiquitous expression of the gene in mouse embryos at stage [https://embryology.med.unsw.edu.au/embryology/index.php/Category:Mouse_E14.5 E14.5] and the adult mouse brain at postnatal days 56 (P56).{{Cite web |title=SLC46A3|url=https://gp3.mpg.de/results/Slc46a3|website=GenePaint}}{{Cite web |title=SLC46A3 (Mouse Brain)|url=https://mouse.brain-map.org/experiment/show?id=386255|website=Allen Brain Atlas}} In the spinal column of juvenile mouse (P4), SLC46A3 is relatively highly expressed in the articular facet, neural arch, and anterior and posterior tubercles.{{Cite web |title=Slc46a3 ISH: Mus musculus, Male, P4, variable|url=http://mousespinal.brain-map.org/imageseries/detail/100006686.html|website=Allen Brain Atlas}} The dorsal horn shows considerable expression in the cervical spine of adult mouse (P56).{{Cite web |title=Slc46a3 ISH: Mus musculus, Male, P56, variable|url=http://mousespinal.brain-map.org/imageseries/detail/100006687.html|website=Allen Brain Atlas}}

RNA-binding proteins (RBPs) that bind to the 5' or 3' UTR regulate mRNA expression by getting involved in RNA processing and modification, nuclear export, localization, and translation.{{cite journal | vauthors = Brinegar AE, Cooper TA | title = Roles for RNA-binding proteins in development and disease | journal = Brain Research | volume = 1647 | pages = 1–8 | date = September 2016 | pmid = 26972534 | pmc = 5003702 | doi = 10.1016/j.brainres.2016.02.050 }} A list of some of the most highly predicted RBPs in conserved regions of the 5' and 3' UTRs are shown below.

Several miRNAs have binding sites in the conserved regions of the 3' UTR of SLC46A3. The following miRNAs can negatively regulate the expression of the mRNA via RNA silencing.{{cite journal | vauthors = Macfarlane LA, Murphy PR | title = MicroRNA: Biogenesis, Function and Role in Cancer | journal = Current Genomics | volume = 11 | issue = 7 | pages = 537–61 | date = November 2010 | pmid = 21532838 | doi = 10.2174/138920210793175895 | pmc = 3048316 }} Silencing mechanisms include mRNA cleavage and translation repression based on the level of complementarity between the miRNA and mRNA target sequences.

File:3'utr_secondary_structure_-_slc46a3.png

The secondary structure of RNA holds both structural and functional significance.{{cite journal | vauthors = Vandivier LE, Anderson SJ, Foley SW, Gregory BD | title = The Conservation and Function of RNA Secondary Structure in Plants | journal = Annual Review of Plant Biology | volume = 67 | issue = 1 | pages = 463–88 | date = April 2016 | pmid = 26865341 | doi = 10.1146/annurev-arplant-043015-111754 | pmc = 5125251 }} Among various secondary structure motifs, the stem-loop structure (hairpin loop) is often conserved across species due to its role in RNA folding, protecting structural stability, and providing recognition sites for RBPs.{{Cite book|date=1993|title=Control of Messenger RNA Stability|doi=10.1016/c2009-0-03269-3|isbn=9780120847822}} The 5' UTR region of SLC46A3 has 7 stem-loop structures identified and 3' UTR region a total of 10.{{cite journal | vauthors = Zuker M | title = Mfold web server for nucleic acid folding and hybridization prediction | journal = Nucleic Acids Research | volume = 31 | issue = 13 | pages = 3406–15 | date = July 2003 | pmid = 12824337 | doi = 10.1093/nar/gkg595 | pmc = 169194 }} The majority of the binding sites of RBPs and miRNAs given above are located at a stem-loop structure, which is also true for the poly(A) signal at the 3' end.

The k-Nearest Neighbor (k-NN) prediction by PSORTII predicts SLC46A3 to be mainly located at the plasma membrane (78.3%) and ER (17.4%), but also possibly at the mitochondrion (4.3%).{{cite book |last1=Nakai|first1=Kenta |last2=Horton|first2=Paul| name-list-style = vanc | chapter =Computational Prediction of Subcellular Localization| title =Protein Targeting Protocols|series=Methods in Molecular Biology |year=2007 |volume=390 |pages=429–466|place=Totowa, NJ|publisher=Humana Press|doi=10.1007/1-59745-466-4_29 |isbn=978-1-58829-702-0}} Immunofluorescent staining of SLC46A3 shows positivity in the plasma membrane, cytoplasm, and actin filaments, although positivity in the latter two is most likely due to the process of the protein being transported by myosin from the ER to the plasma membrane; myosin transports cargo-containing membrane vesicles along actin filaments.{{Cite journal | date=2014|title=The Cell: A Molecular Approach. Sixth Edition. By Geoffrey M. Cooper and Robert E. Hausman. Sunderland (Massachusetts): Sinauer Associates. $142.95. xxv + 832 p.; ill.; index. [A Companion Website is available.] 2013.|isbn=978-0-87893-964-0|journal=The Quarterly Review of Biology|volume=89|issue=4|pages=399|doi=10.1086/678645|issn=0033-5770}}

File:Conceptual_translation_of_human_slc46a3.png

The SLC46A3 protein contains a signal peptide that facilitates co-translational translocation and is cleaved between Thr20 and Gly21.{{cite journal | vauthors = Almagro Armenteros JJ, Tsirigos KD, Sønderby CK, Petersen TN, Winther O, Brunak S, von Heijne G, Nielsen H | s2cid = 216678118 | display-authors = 6 | title = SignalP 5.0 improves signal peptide predictions using deep neural networks | journal = Nature Biotechnology | volume = 37 | issue = 4 | pages = 420–423 | date = April 2019 | pmid = 30778233 | doi = 10.1038/s41587-019-0036-z | url = https://curis.ku.dk/ws/files/248820641/SignalP_5.0_improves_signal_peptide_predictions_using_deep_neural_networks_accepted_version_.pdf }}{{cite journal | vauthors = Käll L, Krogh A, Sonnhammer EL | title = A combined transmembrane topology and signal peptide prediction method | journal = Journal of Molecular Biology | volume = 338 | issue = 5 | pages = 1027–36 | date = May 2004 | pmid = 15111065 | doi = 10.1016/j.jmb.2004.03.016 }} The resulting mature protein, 441 amino acids of length, is subject to further post-translational modifications (PTMs). The sequence has 3 N-glycosylation sites (Asn38, Asn46, Asn53), which are all located in the non-cytoplasmic region flanked by the signal peptide and the first transmembrane domain.{{cite book |last1=Julenius|first1=Karin |last2=Johansen|first2=Morten B.|last3=Zhang|first3=Yu|last4=Brunak|first4=Sren|last5=Gupta|first5=Ramneek | name-list-style = vanc | chapter=Prediction of Glycosylation Sites in Proteins|title =Bioinformatics for Glycobiology and Glycomics|year=2009 |pages=163–192|place=Chichester, UK|publisher=John Wiley & Sons, Ltd|doi=10.1002/9780470029619.ch9 |isbn=978-0-470-02961-9}} Ridigity of the N-terminal region close to the membrane is increased by O-GalNAc at Thr25.{{cite journal | vauthors = Steentoft C, Vakhrushev SY, Joshi HJ, Kong Y, Vester-Christensen MB, Schjoldager KT, Lavrsen K, Dabelsteen S, Pedersen NB, Marcos-Silva L, Gupta R, Bennett EP, Mandel U, Brunak S, Wandall HH, Levery SB, Clausen H | display-authors = 6 | title = Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology | journal = The EMBO Journal | volume = 32 | issue = 10 | pages = 1478–88 | date = May 2013 | pmid = 23584533 | doi = 10.1038/emboj.2013.79 | pmc = 3655468 }}{{Cite book|title=Essentials of glycobiology|others=Varki, Ajit|year = 2017|isbn=978-1-62182-132-8|edition=Third|location=Cold Spring Harbor, New York|oclc=960166742}} O-GlcNAc at sites Ser227, Thr231, Ser445, and Ser459 are involved in the regulation of signaling pathways.{{cite journal | vauthors = Gupta R, Brunak S | title = Prediction of glycosylation across the human proteome and the correlation to protein function | journal = Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing | pages = 310–22 | date = 2001 | pmid = 11928486 | doi = 10.1142/9789812799623_0029 | publisher = WORLD SCIENTIFIC | isbn = 978-981-02-4777-5 }}{{cite journal | vauthors = Fisi V, Miseta A, Nagy T | title = The Role of Stress-Induced O-GlcNAc Protein Modification in the Regulation of Membrane Transport | journal = Oxidative Medicine and Cellular Longevity | volume = 2017 | pages = 1308692 | date = 2017 | pmid = 29456783 | doi = 10.1155/2017/1308692 | pmc = 5804373 | doi-access = free }} In fact, Ser445 and Ser459 are also subject to phosphorylation, where both sites are associated with casein kinase II (CKII), suggesting a crosstalking network that regulates protein activity.{{cite journal | vauthors = Wang C, Xu H, Lin S, Deng W, Zhou J, Zhang Y, Shi Y, Peng D, Xue Y | display-authors = 6 | title = GPS 5.0: An Update on the Prediction of Kinase-specific Phosphorylation Sites in Proteins | journal = Genomics, Proteomics & Bioinformatics | volume = 18 | issue = 1 | pages = 72–80 | date = February 2020 | pmid = 32200042 | doi = 10.1016/j.gpb.2020.01.001 | pmc = 7393560 | doi-access = free }}{{cite journal | vauthors = Blom N, Gammeltoft S, Brunak S | title = Sequence and structure-based prediction of eukaryotic protein phosphorylation sites | journal = Journal of Molecular Biology | volume = 294 | issue = 5 | pages = 1351–62 | date = December 1999 | pmid = 10600390 | doi = 10.1006/jmbi.1999.3310 }}{{cite journal | vauthors = Blom N, Sicheritz-Pontén T, Gupta R, Gammeltoft S, Brunak S | title = Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence | journal = Proteomics | volume = 4 | issue = 6 | pages = 1633–49 | date = June 2004 | pmid = 15174133 | doi = 10.1002/pmic.200300771 | s2cid = 18810164 }} Other highly conserved phosphorylation sites include Thr166, Ser233, Ser253, and Ser454, which are most likely targeted by kinases protein kinase C (PKC), CKII, PKC, and CKI/II, respectively. Conserved glycation sites at epsilon amino groups of lysines are predicted at Lys101, Lys239, and Lys374 with possible disrupting effects on molecular conformation and function of the protein.{{cite journal | vauthors = Johansen MB, Kiemer L, Brunak S | title = Analysis and prediction of mammalian protein glycation | journal = Glycobiology | volume = 16 | issue = 9 | pages = 844–53 | date = September 2006 | pmid = 16762979 | doi = 10.1093/glycob/cwl009 | doi-access = free }}{{cite journal | vauthors = Chen JH, Lin X, Bu C, Zhang X | title = Role of advanced glycation end products in mobility and considerations in possible dietary and nutritional intervention strategies | journal = Nutrition & Metabolism | volume = 15 | issue = 1 | pages = 72 | date = 2018-10-10 | pmid = 30337945 | doi = 10.1186/s12986-018-0306-7 | pmc = 6180645 | doi-access = free }} S-palmitoylation, which help the protein bind more tightly to the membrane by contributing to protein hydrophobicity and membrane association, is predicted at Cys261 and Cys438.{{cite journal | vauthors = Xie Y, Zheng Y, Li H, Luo X, He Z, Cao S, Shi Y, Zhao Q, Xue Y, Zuo Z, Ren J | display-authors = 6 | title = GPS-Lipid: a robust tool for the prediction of multiple lipid modification sites | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 28249 | date = June 2016 | pmid = 27306108 | doi = 10.1038/srep28249 | pmc = 4910163 | bibcode = 2016NatSR...628249X }}{{cite journal | vauthors = Aicart-Ramos C, Valero RA, Rodriguez-Crespo I | title = Protein palmitoylation and subcellular trafficking | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1808 | issue = 12 | pages = 2981–94 | date = December 2011 | pmid = 21819967 | doi = 10.1016/j.bbamem.2011.07.009 | doi-access = free }}{{cite journal | vauthors = Ren J, Wen L, Gao X, Jin C, Xue Y, Yao X | title = CSS-Palm 2.0: an updated software for palmitoylation sites prediction | journal = Protein Engineering, Design & Selection | volume = 21 | issue = 11 | pages = 639–44 | date = November 2008 | pmid = 18753194 | doi = 10.1093/protein/gzn039 | pmc = 2569006 }}{{cite journal | vauthors = Guan X, Fierke CA | title = Understanding Protein Palmitoylation: Biological Significance and Enzymology | journal = Science China Chemistry | volume = 54 | issue = 12 | pages = 1888–1897 | date = December 2011 | pmid = 25419213 | doi = 10.1007/s11426-011-4428-2 | pmc = 4240533 }} S-palmitoylation can also modulate protein-protein interactions of SLC46A3 by changing the affinity of the protein for lipid rafts.

SLC46A1: Also known as the proton-coupled folate transporter, SLC46A3 transports folate and antifolate substrates across cell membranes in a pH-dependent manner.{{Cite web |title=SLC46A1|url=https://www.ncbi.nlm.nih.gov/gene/113235|website=NCBI (National Center for Biotechnology Information) Gene}}

SLC46A2: Aliases include thymic stromal cotransporter homolog, TSCOT, and Ly110. SLC46A2 is involved in symporter activity{{Cite web |title=SLC46A2|url=https://www.ncbi.nlm.nih.gov/gene/57864|website=NCIB (National Center for Biotechnology Information) Gene}} and is a transporter of the immune second messenger 2'3'-cGAMP.{{cite journal |last1=Cordova |first1=Anthony F. |last2=Ritchie |first2=Christopher |last3=Böhnert |first3=Volker |last4=Li |first4=Lingyin |title=Human SLC46A2 Is the Dominant cGAMP Importer in Extracellular cGAMP-Sensing Macrophages and Monocytes |journal=ACS Cent Sci |date=June 23, 2021 |volume=7 |issue=6 |pages=1073–1088 |doi=10.1021/acscentsci.1c00440 |pmid=34235268|pmc=8228594 }}

SLC46A3 is a highly conserved protein with orthologs as distant as fungi. Closely related orthologs have been found in mammals with sequence similarities above 75% while moderately related orthologs come from species of birds, reptiles, amphibians, and fish with sequence similarities of 50-70%. More distantly related orthologs have sequence similarities below 50% and are invertebrates, placozoa, and fungi. The MFS, MFS_1, and transmembrane domains mostly remain conserved throughout species. A selected list of orthologs obtained through NCBI BLAST is shown in the table below.

File:SLC46A3_Protein_Evolution.png

The SLC46A3 gene first appeared in fungi approximately 1105 million years ago (MYA). It evolves at a relatively moderate speed. A 1% change in the protein sequence requires about 6.2 million years. The SLC46A3 gene evolves about 4 times faster than cytochrome c and 2.5 times slower than fibrinogen alpha chain.

As an MFS protein, SLC46A3 is a membrane transporter, mainly involved in the movement of substrates across the lipid bilayer. The protein works via secondary active transport, where the energy for transport is provided by an electrochemical gradient.{{cite journal | vauthors = Pao SS, Paulsen IT, Saier MH | title = Major facilitator superfamily | journal = Microbiology and Molecular Biology Reviews | volume = 62 | issue = 1 | pages = 1–34 | date = March 1998 | pmid = 9529885 | doi = 10.1128/mmbr.62.1.1-34.1998 | pmc = 98904 }}

A proposed function of SLC46A3 of rising importance is the direct transport of maytansine-based catabolites from the lysosome to the cytoplasm by binding the macrolide structure of maytansine.{{cite journal | vauthors = Bissa B, Beedle AM, Govindarajan R | title = Lysosomal solute carrier transporters gain momentum in research | journal = Clinical Pharmacology and Therapeutics | volume = 100 | issue = 5 | pages = 431–436 | date = November 2016 | pmid = 27530302 | doi = 10.1002/cpt.450 | pmc = 5056150 }} Among the different types of antibody-drug conjugates (ADCs), maytansine-based noncleavable linker ADC catabolites, such as lysine-MCC-DM1, are particularly responsive to SLC46A3 activity. The protein functions independent of the cell surface target or cell line, thus is most likely to recognize maytansine or a moiety within the maytansine scaffold. Through transmembrane transport activity, the protein regulates catabolite concentration in the lysosome. In addition, SLC46A3 expression has been identified as a mechanism for resistance to ADCs with noncleavable maytansinoid and pyrrolobenzodiazepine warheads.{{cite journal | vauthors = Kinneer K, Meekin J, Tiberghien AC, Tai YT, Phipps S, Kiefer CM, Rebelatto MC, Dimasi N, Moriarty A, Papadopoulos KP, Sridhar S, Gregson SJ, Wick MJ, Masterson L, Anderson KC, Herbst R, Howard PW, Tice DA | display-authors = 6 | title = SLC46A3 as a Potential Predictive Biomarker for Antibody-Drug Conjugates Bearing Noncleavable Linked Maytansinoid and Pyrrolobenzodiazepine Warheads | journal = Clinical Cancer Research | volume = 24 | issue = 24 | pages = 6570–6582 | date = December 2018 | pmid = 30131388 | doi = 10.1158/1078-0432.ccr-18-1300 | doi-access = free }} Although subcellular localization predictions have failed to identify the lysosome as a final destination of the protein, the YXXphi motif identified in the protein sequence has shown to direct lysosomal sorting.

SLC46A3 may be involved in plasma membrane electron transport (PMET), a plasma membrane analog of the mitochondrial electron transport chain (ETC) that oxidizes intracellular NADH and contributes to aerobic energy production by supporting glycolytic ATP production.{{cite journal | vauthors = Herst PM, Berridge MV | title = Plasma membrane electron transport: a new target for cancer drug development | journal = Current Molecular Medicine | volume = 6 | issue = 8 | pages = 895–904 | date = December 2006 | pmid = 17168740 | doi = 10.2174/156652406779010777 | url = https://www.eurekaselect.com/58264/article | access-date = 2020-08-01 }} The 3' UTR region of SLC46A3 includes a binding site for ENOX1, a protein highly involved in PMET.{{Cite web |title=ENOX1 ecto-NOX disulfide-thiol exchanger 1 [ Homo sapiens (human) ]|url=https://www.ncbi.nlm.nih.gov/gene/55068|website=NCBI (National Center for Biotechnology Information) Gene}} The C-(X)₂-C motif in the protein sequence also suggests possible oxidoreductase activity.

SLC46A3 has been found to generally interact with proteins involved in membrane transport, immune response, catalytic activity, or oxidation of substrates.{{Cite journal|title=Figure S6: Predicted secondary structure of CoV-RMEN using CFSSP:Chou and Fasman secondary structure prediction server|doi=10.7717/peerj.9572/supp-13|doi-access=free}} Some of the most definite and clinically important interactions include the following proteins.

• CD79A: An interaction with CD79A was identified in a yeast-two hybrid (Y2H) screen with a confidence score of 0.632 by the human binary protein interactome (HuRI).{{cite journal | vauthors = Luck K, Kim DK, Lambourne L, Spirohn K, Begg BE, Bian W, Brignall R, Cafarelli T, Campos-Laborie FJ, Charloteaux B, Choi D, Coté AG, Daley M, Deimling S, Desbuleux A, Dricot A, Gebbia M, Hardy MF, Kishore N, Knapp JJ, Kovács IA, Lemmens I, Mee MW, Mellor JC, Pollis C, Pons C, Richardson AD, Schlabach S, Teeking B, Yadav A, Babor M, Balcha D, Basha O, Bowman-Colin C, Chin SF, Choi SG, Colabella C, Coppin G, D'Amata C, De Ridder D, De Rouck S, Duran-Frigola M, Ennajdaoui H, Goebels F, Goehring L, Gopal A, Haddad G, Hatchi E, Helmy M, Jacob Y, Kassa Y, Landini S, Li R, van Lieshout N, MacWilliams A, Markey D, Paulson JN, Rangarajan S, Rasla J, Rayhan A, Rolland T, San-Miguel A, Shen Y, Sheykhkarimli D, Sheynkman GM, Simonovsky E, Taşan M, Tejeda A, Tropepe V, Twizere JC, Wang Y, Weatheritt RJ, Weile J, Xia Y, Yang X, Yeger-Lotem E, Zhong Q, Aloy P, Bader GD, De Las Rivas J, Gaudet S, Hao T, Rak J, Tavernier J, Hill DE, Vidal M, Roth FP, Calderwood MA | display-authors = 6 | title = A reference map of the human binary protein interactome | journal = Nature | volume = 580 | issue = 7803 | pages = 402–408 | date = April 2020 | pmid = 32296183 | pmc = 7169983 | doi = 10.1038/s41586-020-2188-x | bibcode = 2020Natur.580..402L }} Also known as B-cell antigen receptor complex-associated protein alpha chain, CD79A, together with CD79B, forms the B-cell antigen receptor (BCR) by covalently associating with surface immunoglobulin (Ig).{{Cite web |title=CD79A CD79a molecule [ Homo sapiens (human) ]|url=https://www.ncbi.nlm.nih.gov/gene/973|website=NCBI (National Center for Biotechnology Information) Gene}} The BCR responds to antigens and initiates signal transduction cascades.{{Cite web |title=P11912 (CD79A_HUMAN)|url=https://www.uniprot.org/uniprot/P11912|website=UniProt}}
• LGALS3: High-throughput affinity purification-mass spectrometry (AP-MS) identified an interaction between SLC46A3 and LGALS3 with an interaction score of 0.761, classified as high-confidence interacting proteins (HCIPs) by CompPASS-Plus.{{cite journal | vauthors = Huttlin EL, Ting L, Bruckner RJ, Gebreab F, Gygi MP, Szpyt J, Tam S, Zarraga G, Colby G, Baltier K, Dong R, Guarani V, Vaites LP, Ordureau A, Rad R, Erickson BK, Wühr M, Chick J, Zhai B, Kolippakkam D, Mintseris J, Obar RA, Harris T, Artavanis-Tsakonas S, Sowa ME, De Camilli P, Paulo JA, Harper JW, Gygi SP | display-authors = 6 | title = The BioPlex Network: A Systematic Exploration of the Human Interactome | journal = Cell | volume = 162 | issue = 2 | pages = 425–440 | date = July 2015 | pmid = 26186194 | doi = 10.1016/j.cell.2015.06.043 | pmc = 4617211 }} Also known as galectin-3 (Gal3), LGALS3 participates in various cellular functions including apoptosis, innate immunity, cell adhesion, and T-cell regulation.{{Cite web |title=LGALS3 galectin 3 [ Homo sapiens (human) ]|url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=3958|website=NCBI (National Center for Biotechnology Information) Gene}} The protein is involved in antimicrobial activity against bacteria and fungi and has been identified as a negative regulator of mast cell degranulation. LGALS3 is highly upregulated in glioblastoma tissue and brains of Altzheimer's disease patients.
• NSP2: A high-throughput Y2H screening of the SARS-CoV ORFeome and host proteins isolated a single-hit interaction between NSP2 and SLC46A3 with a LUMIER z-score of -0.5. Short for non-structural protein 2, NSP2 is one of the many non-structural proteins encoded in the orf1ab polyprotein.{{cite book | vauthors = Graham RL, Sims AC, Baric RS, Denison MR | title = The Nidoviruses | chapter = The NSP2 Proteins of Mouse Hepatitis Virus and Sars Coronavirus are Dispensable for Viral Replication | series = Advances in Experimental Medicine and Biology | volume = 581 | pages = 67–72 | date = 2006 | pmid = 17037506 | doi = 10.1007/978-0-387-33012-9_10 | publisher = Springer US | pmc = 7123188 | isbn = 978-0-387-26202-4 | place = Boston, MA }}{{Cite journal|date=2020-04-07|title=Review for "Therapeutic uncertainties in people with cardiometabolic diseases and severe acute respiratory syndrome coronavirus 2 ( SARS-CoV -2 or COVID -19)"|doi=10.1111/dom.14062/v1/review3|s2cid=219115750 }} NSP2 alters the host cell environment rather than contribute directly to viral replication. The protein interacts with prohibitin 1 (PHB1) and PHB2.

SNPs are a very common type of genetic variation and are silent most of the time.{{cite journal | vauthors = Shen LX, Basilion JP, Stanton VP | title = Single-nucleotide polymorphisms can cause different structural folds of mRNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 14 | pages = 7871–6 | date = July 1999 | pmid = 10393914 | doi = 10.1073/pnas.96.14.7871 | pmc = 22154 | bibcode = 1999PNAS...96.7871S | doi-access = free }} However, certain SNPs in the conserved or functionally important regions of the gene may have adverse effects on gene expression and function. Some of the SNPs with potentially damaging effects identified in the coding sequence of SLC46A3 are shown in the table below.

f*The coordinates/positions are for GRCh38.p7.

The clinical significance of SLC46A3 surrounds the protein's activity as a transporter of maytansine-based ADC catabolites. shRNA screens employing two libraries identified SLC46A3 as the only hit as a mediator of noncleavable maytansine-based ADC-dependent cytotoxicity, with q-values of 1.18×10⁻⁹ and 9.01×10⁻³. Studies show either lost or significantly reduced SLC46A3 expression (-2.79 fold decrease by microarray with p-value 5.80×10⁻⁸) in T-DM1 (DM1 payload attached to antibody trastuzumab)-resistant breast cancer cells (KPL-4 TR). In addition, siRNA knockdown in human breast tumor cell line BT-474M1 also results in resistance to T-DM1. Such association between loss of SLC46A3 expression and resistance to ADCs also applies to pyrrolobenzodiazepine warheads, signifying the important role of SLC46A3 in cancer treatment.

CDP, one of SLC46A3's transcription factors, works as a tumor suppressor where CDP deficiency activates phosphoinositide 3-kinase (PI3K) signaling that leads to tumor growth.{{cite journal | vauthors = Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C, Alexandrov LB, Tiffen JC, Kober C, Green AR, Massie CE, Nangalia J, Lempidaki S, Döhner H, Döhner K, Bray SJ, McDermott U, Papaemmanuil E, Campbell PJ, Adams DJ | display-authors = 6 | title = Inactivating CUX1 mutations promote tumorigenesis | journal = Nature Genetics | volume = 46 | issue = 1 | pages = 33–8 | date = January 2014 | pmid = 24316979 | doi = 10.1038/ng.2846 | pmc = 3874239 }} The loss of heterozygosity and mutations of CDP are also associated with a variety of cancers.{{cite journal | vauthors = Liu N, Sun Q, Wan L, Wang X, Feng Y, Luo J, Wu H | title = CUX1, A Controversial Player in Tumor Development | journal = Frontiers in Oncology | volume = 10 | pages = 738 | date = 2020-05-29 | pmid = 32547943 | doi = 10.3389/fonc.2020.00738 | pmc = 7272708 | doi-access = free }}

Microarray analysis of SLC46A3 in two different prostate cancer cell lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), show SLC46A3 expression in DU145 to be about 5 times as high as in LNCaP for percentile ranks and 1.5 times as high for transformed counts, demonstrating an association between SLC46A3 and accelerated cell growth of prostate cancer cells. SLC46A3 possibly contributes to the androgen-independent manner of cancer development.

SLC46A3 was found to be down-regulated in 83.2% of human HCC tissues based on western blot scores and qRT-PCR results on mRNA expression (p < 0.0001). Overexpression of the gene also reduced resistance to sorafenib treatment and improved overall survival rate (p = 0.00085).

Western blot analysis supports substantially strong expression of SLC46A3 in papilloma and glioma cells when compared to expression in the liver, one of the organs where the gene is most highly expressed.

A genome-wide association study on obesity identified 10 variants in the flanking 5′UTR region of SLC46A3 that were highly associated with diet fat (% energy) (p = 1.36×10⁻⁶ - 9.57×10⁻⁶). In diet-induced obese (DIO) mice, SLC46A3 shows decreased gene expression following c-Jun N-terminal kinase 1 (JNK1) depletion, suggesting possible roles in insulin resistance as well as glucose/triglyceride homeostasis.{{cite journal | vauthors = Yang R, Wilcox DM, Haasch DL, Jung PM, Nguyen PT, Voorbach MJ, Doktor S, Brodjian S, Bush EN, Lin E, Jacobson PB, Collins CA, Landschulz KT, Trevillyan JM, Rondinone CM, Surowy TK | display-authors = 6 | title = Liver-specific knockdown of JNK1 up-regulates proliferator-activated receptor gamma coactivator 1 beta and increases plasma triglyceride despite reduced glucose and insulin levels in diet-induced obese mice | journal = The Journal of Biological Chemistry | volume = 282 | issue = 31 | pages = 22765–74 | date = August 2007 | pmid = 17550900 | doi = 10.1074/jbc.m700790200 | doi-access = free }}

Understanding the interaction between SLC46A3 and NSP2 in addition to the functions of each protein is critical to gaining insight into the pathogenesis of coronaviruses, namely SARS-CoV and SARS-CoV-2. The NSP2 protein domain resides in a region of the coronavirus replicase that is not particularly conserved across coronaviruses, and thus the altering protein sequence leads to significant changes in protein structure, leading to structural and functional variability.

• Solute carrier family

== References ==

{{reflist}}

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{{refend}}

Category:Human proteins