Major Facilitator Superfamily; The Major Facilitator Superfamily (MFS) is a large and diverse group of secondary transporters that includes uniporters, symporters, and antiporters. MFS proteins facilitate the transport across cytoplasmic or internal membranes of a variety of substrates including ions, sugar phosphates, drugs, neurotransmitters, nucleosides, amino acids, and peptides. They do so using the electrochemical potential of the transported substrates. Uniporters transport a single substrate, while symporters and antiporters transport two substrates in the same or in opposite directions, respectively, across membranes. MFS proteins are typically 400 to 600 amino acids in length, and the majority contain 12 transmembrane alpha helices (TMs) connected by hydrophilic loops. The N- and C-terminal halves of these proteins display weak similarity and may be the result of a gene duplication/fusion event. Based on kinetic studies and the structures of a few bacterial superfamily members, GlpT (glycerol-3-phosphate transporter), LacY (lactose permease), and EmrD (multidrug transporter), MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement. Bacterial members function primarily for nutrient uptake, and as drug-efflux pumps to confer antibiotic resistance. Some MFS proteins have medical significance in humans such as the glucose transporter Glut4, which is impaired in type II diabetes, and glucose-6-phosphate transporter (G6PT), which causes glycogen storage disease when mutated.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2411815800   1 MKVASIFLLTALVLMSLSG--------NSGANILGREAKCTNEVNgCPR-IYNPVCGTDGVTYANEC 58
Cdd:cd17461   335 ILSISIMLCVPLFFMGCSTqdvagvypKTSNSSDGPHLSCSANCS-CPEsAFNPVCGENGIEYISPC 400

Kazal-type serine protease inhibitor domain; Usually indicative of serine protease inhibitors. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors. Kazal domains often occur in tandem arrays. Small alpha+beta fold containing three disulphides. Alignment also includes a single domain from transporters in the OATP/PGT family.

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                 ....*....|....*....|....*....|....*....|....*....
gi 2411815800 32 CTNEVNG-CPRIYNPVCGTDGVTYANECLLCMENKERQTPVLIQKSGPC 79
Cdd:pfam00050  1 CSDYPSGaCPRIYDPVCGTDGKTYSNECLFCAENGKRGTNLHKVHDGEC 49

Solute carrier organic anion transporter 2A subfamily of the Major Facilitator Superfamily of transporters; The Solute carrier organic anion transporter 2A (SLCO2A), also called Organic anion-transporting polypeptide 2A (OATP2A), subfamily has one mammalian member, OATP2A1 (encoded by SLCO2A1), which is also called prostaglandin transporter. It is a lactate/prostaglandin anion exchanger that mediates the release of newly synthesized prostaglandins (PGD2, PGE1, PGE2, PGF2A and PGI2) from cells, the transepithelial transport of prostaglandins, and the clearance of prostaglandins from the circulation. Mutations in SLCO2A1 can cause primary hypertrophic osteoarthropathy (PHO), a rare multi-organic disease characterized by digital clubbing, pachydermia and periosteal reaction. The SLCO2A/OATP2A subfamily belongs to the Solute carrier organic anion transporter [SLCO, also called organic anion transporting polypeptides (OATPs) or Solute carrier family 21] family of the Major Facilitator Superfamily (MFS) of transporters. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2411815800   1 MKVASIFLLTALVLMSLSG--------NSGANILGREAKCTNEVNgCPR-IYNPVCGTDGVTYANEC 58
Cdd:cd17461   335 ILSISIMLCVPLFFMGCSTqdvagvypKTSNSSDGPHLSCSANCS-CPEsAFNPVCGENGIEYISPC 400

Kazal-type serine protease inhibitor domain; Usually indicative of serine protease inhibitors. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors. Kazal domains often occur in tandem arrays. Small alpha+beta fold containing three disulphides. Alignment also includes a single domain from transporters in the OATP/PGT family.

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                 ....*....|....*....|....*....|....*....|....*....
gi 2411815800 32 CTNEVNG-CPRIYNPVCGTDGVTYANECLLCMENKERQTPVLIQKSGPC 79
Cdd:pfam00050  1 CSDYPSGaCPRIYDPVCGTDGKTYSNECLFCAENGKRGTNLHKVHDGEC 49

Kazal type serine protease inhibitors and follistatin-like domains. Kazal inhibitors inhibit serine proteases, such as, trypsin, chyomotrypsin, avian ovomucoids, and elastases. The inhibitory domain has one reactive site peptide bond, which serves the cognate enzyme as substrate. The reactive site peptide bond is a combining loop which has an identical conformation in all Kazal inhibitors and in all enzyme/inhibitor complexes. These Kazal domains (small hydrophobic core of alpha/beta structure with 3 to 4 disulfide bonds) often occur in tandem arrays. Similar domains are also present in follistatin (FS) and follistatin-like family members, which play an important role in tissue specific regulation. The FS domain consists of an N-terminal beta hairpin (FOLN/EGF-like domain) and a Kazal-like domain and has five disulfide bonds. Although the Kazal-like FS substructure is similar to Kazal proteinase inhibitors, no FS domain has yet been shown to be a proteinase inhibitor. Follistatin-like family members include SPARC, also known as, BM-40 or osteonectin, the Gallus gallus Flik protein, as well as, agrin which has a long array of FS domains. The kazal-type inhibitor domain has also been detected in an extracellular loop region of solute carrier 21 (SLC21) family members (organic anion transporters) , which may regulate the specificity of anion uptake. The distant homolog, Ascidian trypsin inhibitor, is included in this CD.

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                 ....*....|....*....|....*....|....*....|.
gi 2411815800 39 CPRIYNPVCGTDGVTYANECLLCMENKERQTPVLIQKSGPC 79
Cdd:cd00104    1 CPKEYDPVCGSDGKTYSNECHLGCAACRSGRSITVAHNGPC 41

Solute carrier organic anion transporter 3 family of the Major Facilitator Superfamily of transporters; The Solute carrier organic anion transporter 3 (SLCO3) or Organic anion transporting polypeptide 3 (OATP3) family contains only one subfamily, OATP3A, which contains only one mammalian member OATP3A1 (encoded by SLCO3A1). It mediates the Na(+)-independent transport of organic anions such as estrone-3-sulfate, prostaglandins (PG) E1 and E2, thyroxine (T4), deltorphin II, BQ-123, and vasopressin. SLCO3A1 has been identified as a Crohn's disease (CD)-associated gene, which mediates inflammatory processes in intestinal epithelial cells through NF-kappaB transcription activation, resulting in a higher incidence of bowel perforation in CD patients. The SLCO3/OATP3 family belongs to the Solute carrier organic anion transporter [SLCO, also called organic anion transporting polypeptides (OATPs) or Solute carrier family 21] family of the Major Facilitator Superfamily (MFS) of transporters. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

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                  ....*....|....*....|....*....|....
gi 2411815800  26 LGREAKCTNEVNGCPRIYNPVCGTDGVTYANECL 59
Cdd:cd17402   346 LDPYAPCNSNCECQTDSFSPVCGADGITYLSACF 379

Solute carrier organic anion transporter 4A subfamily of the Major Facilitator Superfamily of transporters; The Solute carrier organic anion transporter 4A (SLCO4A), also called Organic anion-transporting polypeptide 4A (OATP4A), subfamily has one mammalian member, OATP4A1 (encoded by SLCO4A1). It is ubiquitously expressed and it mediates the Na(+)-independent transport of the thyroid hormones T3 (triiodo-L-thyronine), T4 (thyroxine) and rT3, and other organic anions such as estrone sulfate and taurocholate. OATP4A1 is the most abundantly expressed transporter colorectal cancer (CRC) and its role in the transport of estrone sulfate, which is used in hormone replacement therapy (HRT), affects the outcome of the treatment. The SLCO4A/OATP4A subfamily belongs to the Solute carrier organic anion transporter [SLCO, also called organic anion transporting polypeptides (OATPs) or Solute carrier family 21] family of the Major Facilitator Superfamily (MFS) of transporters. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

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gi 2411815800  30 AKCTNEVNGCPRIYNPVCGTDGVTYANEC 58
Cdd:cd17462   325 ALCNADCRCLEEIYSPVCGADGLMYYSPC 353