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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               ....*....|....*....|....*....|....*....|.
1LDT_L       6 CPKILKPVCGSDGRTYANSCIARC------NGVSIKSEGSC 40
Cdd:cd00104  1 CPKEYDPVCGSDGKTYSNECHLGCaacrsgRSITVAHNGPC 41

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.

                       10        20        30        40
               ....*....|....*....|....*....|....*....|.
1LDT_L       6 CPKILKPVCGSDGRTYANSCIARC------NGVSIKSEGSC 40
Cdd:cd00104  1 CPKEYDPVCGSDGKTYSNECHLGCaacrsgRSITVAHNGPC 41

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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                 ....*....|....*....|..
1LDT_L         5 ACPKILKPVCGSDGRTYANSCI 26
Cdd:pfam00050  8 ACPRIYDPVCGTDGKTYSNECL 29

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.

                       10        20        30        40
               ....*....|....*....|....*....|....*....|.
1LDT_L       6 CPKILKPVCGSDGRTYANSCIARC------NGVSIKSEGSC 40
Cdd:cd00104  1 CPKEYDPVCGSDGKTYSNECHLGCaacrsgRSITVAHNGPC 41

Kazal-type pancreatic secretory trypsin inhibitors (PSTI) and related proteins, including the second domain of the ovomucoid turkey inhibitor and the C-terminal domain of the esophagus cancer-related gene-2 protein (ECRG-2), are members of the superfamily of kazal-type proteinase inhibitors and follistatin-like proteins.

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               ....*....|....*....|....*....|....*....|..
1LDT_L       5 ACPKILKPVCGSDGRTYANSC------IARCNGVSIKSEGSC 40
Cdd:cd01327  4 GCPKDYDPVCGTDGVTYSNECllcaenLKRQTNIRIKHDGEC 45

Solute carrier organic anion transporters of the Major Facilitator Superfamily of transporters; Solute carrier organic anion transporters (SLCOs) are also called organic anion transporting polypeptides (OATPs) or SLC21 (Solute carrier family 21) proteins. They are sodium-independent transporters that mediate the transport of a broad range of endo- as well as xenobiotics. Their substrates are mainly amphipathic organic anions with a molecular weight of more than 300Da, although there are a few known neutral or positively charged substrates. These include drugs including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensives, and anticancer drugs. SLCOs/OATPs can be classified into 6 families (SLCO1-6 or OATP1-6) and each family may have subfamilies (e.g. OATP1A, OATP1B, OATP1C). Within the subfamilies, individual members are numbered according to the chronology of their identification and if there is already an ortholog known, they are given the same number. For example, the first SLCO identified, is rat OATP1A1 (encoded by the Slco1a1 gene). The second SLCO identified is the first human SLCO from the same subfamily and is called OATP1A2 (encoded by the SLCO1A2 gene). There are 11 human SLCOs/OATPs. SLCOs belong to the Major Facilitator Superfamily (MFS) of membrane transport proteins, which are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

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                ....*....|....*....|....*....|....
1LDT_L        4 CACPKIL-KPVCGSDGRTYANSCIARCNGVSIKS 36
Cdd:cd17336 316 CNCSDSSfSPVCGSDGITYFSPCHAGCTSSDAGN 349

Solute carrier organic anion transporter 5 family of the Major Facilitator Superfamily of transporters; The Solute carrier organic anion transporter 5 (SLCO5) or Organic anion transporting polypeptide 5 (OATP5) family contains only one subfamily, OATP5A, which contains only one mammalian member OATP5A1 (encoded by SLCO5A1). Deletion of the SLCO5A1 gene has been implicated in the pathogenesis of Mesomelia-synostoses syndrome (MSS), a rare autosomal-dominant disorder characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations. OATP5A1 may be a non-classical OATP which is involved in biological processes that require the reorganization of the cell shape, such as differentiation and migration. It seems to affect intracellular transport of drugs and may participate in chemoresistance of small cell lung cancer (SCLC by sequestration), rather than mediating cellular uptake. The SLCO5/OATP5 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.

                        10        20        30
                ....*....|....*....|....*....|....*.
1LDT_L        4 CACP-KILKPVCGSDGRTYANSCIARCNGVSIKSEG 38
Cdd:cd17404 324 CGCSiNEYEPVCGSDGITYFSPCLAGCTSVGNTSTG 359

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.

                        10        20        30
                ....*....|....*....|....*....|....
1LDT_L        4 CACPK-ILKPVCGSDGRTYANSCIARCNGVSIKS 36
Cdd:cd17461 378 CSCPEsAFNPVCGENGIEYISPCHAGCTNSNMDS 411

Solute carrier organic anion transporter 1C subfamily of the Major Facilitator Superfamily of transporters; The Solute carrier organic anion transporter 1C (SLCO1C), also called Organic anion-transporting polypeptide 1C (OATP1C), subfamily contains one mammalian member, OATP1C1 (encoded by SLCO1C1), which is also called thyroxine transporter. It mediates the high affinity transport of the thyroid hormones, T4 (3,5,3',5'tetraiodo-L-thyronine or thyroxine), rT3 (3,3'5'-triiodo-L-thyronine), and T3 (3,5,3'tri-iodo-L-thyronine or triiodothyronine), as well as organic anions such as 17-beta-glucuronosyl estradiol, estrone-3-sulfate, and sulfobromophthalein (BSP), which are transported with much lower efficiency. The SLCO1C/OATP1C 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.

                        10        20
                ....*....|....*....|....*...
1LDT_L        3 VCACP-KILKPVCGSDGRTYANSCIARC 29
Cdd:cd17459 398 DCKCSqKDWDPVCGENGITYVSPCLAGC 425

Solute carrier organic anion transporter 1 family of the Major Facilitator Superfamily of transporters; The Solute carrier organic anion transporter 1 (SLCO1) or Organic anion transporting polypeptide 1 (OATP1) family contains three subfamilies: OATP1A, OATP1B, and OATP1C. OATP1A contains one human member, OATP1A2, which shows a broad spectrum of substrates including endogenous compounds (such as bile acids, steroid hormones and their conjugates, thyroid hormones) and various drugs (such as fexofenadine, ouabain and the cyanobacterial toxin microcystin). OATP1B contains two human proteins, OATP1B1 and OATP1B3, which can both accept a wide variety of structurally-unrelated compounds as substrates including clinically-important drugs such as hydroxymethylglutaryl (HMG)-CoA reductase inhibitors (statins), angiotensin II receptor blockers (sartans), angiotensin converting enzyme (ACE) inhibitors, and anti-diabetes drugs (glinides). OATP1C contains one mammalian member, OATP1C1, which is also called thyroxine transporter. It mediates the high affinity transport of the thyroid hormones, T4 (3,5,3',5'tetraiodo-L-thyronine or thyroxine), rT3 (3,3'5'-triiodo-L-thyronine), and T3 (3,5,3'tri-iodo-L-thyronine or triiodothyronine). The SLCO1/OATP1 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.

                        10        20
                ....*....|....*....|....*..
1LDT_L        4 CACP-KILKPVCGSDGRTYANSCIARC 29
Cdd:cd17400 338 CNCPeKIWEPVCGNNGITYLSACLAGC 364

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.

                        10        20        30
                ....*....|....*....|....*....|..
1LDT_L        4 CAC-PKILKPVCGSDGRTYANSCIARCNGVSI 34
Cdd:cd17402 356 CECqTDSFSPVCGADGITYLSACFAGCSSTNL 387