NTR_like domain; a beta barrel with an oligosaccharide/oligonucleotide-binding fold found in netrins, complement proteins, tissue inhibitors of metalloproteases (TIMP), and procollagen C-proteinase enhancers (PCOLCE), amongst others. In netrins, the domain plays a role in controlling axon branching in neural development, while the common function of these modules in TIMPs appears to be binding to metzincins. A subset of this family is also known as the C345C domain because it occurs as a C-terminal domain in complement C3, C4 and C5. In C5, the domain interacts with various partners during the formation of the membrane attack complex.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 209862949 431 ALSLCRSDFAIVGRLTEVLEEPEaaGGIARVALDDVLKDDKMGLKFLGTKYLEVTLSGMDWACPCPNVTVGDGPLVIMGE 510
Cdd:cd03575    1 VPSLCRSDFAIVGRLTELTEELD--SGHARVTLEEVLKDEKMGLKFFGTEPLEVTLLNMDWSCPCPNITAGEGPLIIMGD 78

                         90       100       110
                 ....*....|....*....|....*....|.
gi 209862949 511 VREGVAVLDANSYVRAASEKRVKKIVELLEK 541
Cdd:cd03575   79 VHDGMAVLQPDSYVRASSERRVRKLREVLHK 109

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 209862949 362 VCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDACP 414
Cdd:cd22606    1 ICSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDACP 53

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
                 ....*....|....*....|....*....|....*.
gi 209862949 124 CEKEPSFTCASDGLTYYNRCYMDAEACLRGLHLHVV 159
Cdd:cd00104    1 CPKEYDPVCGSDGKTYSNECHLGCAACRSGRSITVA 36

NTR domain, WFIKKN subfamily; WFIKKN proteins contain a C-terminal NTR domain and are putative secreted proteins which may be multivalent protease inhibitors that act on serine proteases as well as metalloproteases. Human WFIKKN and a related protein sharing the same domain architecture were observed to have distinct tissue expression patterns. WFIKKN is also referred to as growth and differentiation factor-associated serum protein-1 (GASP-1). It inhibits the activity of mature myostatin, a specific regulator of skeletal muscle mass and a member of the TGFbeta superfamily.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 209862949 431 ALSLCRSDFAIVGRLTEVLEEPEaaGGIARVALDDVLKDDKMGLKFLGTKYLEVTLSGMDWACPCPNVTVGDGPLVIMGE 510
Cdd:cd03575    1 VPSLCRSDFAIVGRLTELTEELD--SGHARVTLEEVLKDEKMGLKFFGTEPLEVTLLNMDWSCPCPNITAGEGPLIIMGD 78

                         90       100       110
                 ....*....|....*....|....*....|.
gi 209862949 511 VREGVAVLDANSYVRAASEKRVKKIVELLEK 541
Cdd:cd03575   79 VHDGMAVLQPDSYVRASSERRVRKLREVLHK 109

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 209862949 362 VCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDACP 414
Cdd:cd22606    1 ICSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDACP 53

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 209862949  362 VCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:pfam00014   1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTC 52

Immunoglobulin like; IG domains that cannot be classified into one of IGv1, IGc1, IGc2, IG.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 209862949   196 PSPQAVHVGGTASLHCDVSGRPPPAVTWEKQSHQrenLIMRPDQMYGnVVVTSIGQLVLYNAQLEDAGLYTCTARNAAGL 275
Cdd:smart00410   1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGK---LLAESGRFSV-SRSGSTSTLTISNVTPEDSGTYTCAATNSSGS 76

                   ....*....
gi 209862949   276 LRADFPLSV 284
Cdd:smart00410  77 ASSGTTLTV 85

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
                 ....*....|....*....|....*....|....*.
gi 209862949 124 CEKEPSFTCASDGLTYYNRCYMDAEACLRGLHLHVV 159
Cdd:cd00104    1 CPKEYDPVCGSDGKTYSNECHLGCAACRSGRSITVA 36

UNC-6/NTR/C345C module; Sequence similarity between netrin UNC-6 and C345C complement protein family members, and hence the existence of the UNC-6 module, was first reported in. Subsequently, many additional members of the family were identified on the basis of sequence similarity between the C-terminal domains of netrins, complement proteins C3, C4, C5, secreted frizzled-related proteins, and type I pro-collagen C-proteinase enhancer proteins (PCOLCEs), which are homologous with the N-terminal domains of tissue inhibitors of metalloproteinases (TIMPs). The TIMPs are classified as a separate family in Pfam (pfam00965). This expanded domain family has been named as the NTR module.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 209862949  436 RSDFAIVGRLTEVLEEPEAAggIARVALDDVLK--DDKmglKFLGTKYLEVTlsgmDWACPCPNVTVGDgPLVIMGEVRE 513
Cdd:pfam01759   6 GSDYVYKVKVLSVEEEGSFD--KYTVKVKEVLKegTDK---IQRGKVRLFLK----RGDCRCPQLRLGK-EYLIMGKVGD 75

                          90       100
                  ....*....|....*....|....*....
gi 209862949  514 GV----AVLDANSYVRAASEKRVKKIVEL 538
Cdd:pfam01759  76 LEgrgrYVLDKNSWVEPWPTKWECKLREL 104

Kazal type serine protease inhibitors; Kazal type serine protease inhibitors and follistatin-like domains.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 209862949   120 CRDRCEKEPSFTCASDGLTYYNRCYMDAEACLRGLHLHVV 159
Cdd:smart00280   2 CPEACPREYDPVCGSDGVTYSNECHLCKAACESGKSIEVK 41

NTR domain, WFIKKN subfamily; WFIKKN proteins contain a C-terminal NTR domain and are putative secreted proteins which may be multivalent protease inhibitors that act on serine proteases as well as metalloproteases. Human WFIKKN and a related protein sharing the same domain architecture were observed to have distinct tissue expression patterns. WFIKKN is also referred to as growth and differentiation factor-associated serum protein-1 (GASP-1). It inhibits the activity of mature myostatin, a specific regulator of skeletal muscle mass and a member of the TGFbeta superfamily.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 209862949 431 ALSLCRSDFAIVGRLTEVLEEPEaaGGIARVALDDVLKDDKMGLKFLGTKYLEVTLSGMDWACPCPNVTVGDGPLVIMGE 510
Cdd:cd03575    1 VPSLCRSDFAIVGRLTELTEELD--SGHARVTLEEVLKDEKMGLKFFGTEPLEVTLLNMDWSCPCPNITAGEGPLIIMGD 78

                         90       100       110
                 ....*....|....*....|....*....|.
gi 209862949 511 VREGVAVLDANSYVRAASEKRVKKIVELLEK 541
Cdd:cd03575   79 VHDGMAVLQPDSYVRASSERRVRKLREVLHK 109

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 209862949 362 VCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDACP 414
Cdd:cd22606    1 ICSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDACP 53

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 209862949  362 VCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:pfam00014   1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTC 52

Kunitz domain 2 of hepatocyte growth factor activator inhibitor-1 (HAI1); This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 1 (HAI-1 or HAI1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. While the Kunitz domain 1 (KD1) is the major inhibitory domain of HAI-1 and involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure, studies show that deletion of HAI-1 Kunitz domain 2 (KD2) and the extracellular region enhanced inhibition of matriptase. HAI-1 KD2 has been shown to have potent inhibitory activity against trypsin, but it cannot inhibit hepatocyte growth factor activator (HGFA), and matriptase. HAI-1 is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structure of KD2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 209862949 363 CALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22624    2 CTEPPVTGPCRASFTRWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETC 52

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 209862949  189 PPALYNSPSPQAVHVGGTASLHCDVSGRPPPAVTWEKQSHQRENLIMRPDQMYGNVvvtsiGQLVLYNAQLEDAGLYTCT 268
Cdd:pfam13927   1 KPVITVSPSSVTVREGETVTLTCEATGSPPPTITWYKNGEPISSGSTRSRSLSGSN-----STLTISNVTRSDAGTYTCV 75

                  ...
gi 209862949  269 ARN 271
Cdd:pfam13927  76 ASN 78

Immunoglobulin like; IG domains that cannot be classified into one of IGv1, IGc1, IGc2, IG.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 209862949   196 PSPQAVHVGGTASLHCDVSGRPPPAVTWEKQSHQrenLIMRPDQMYGnVVVTSIGQLVLYNAQLEDAGLYTCTARNAAGL 275
Cdd:smart00410   1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGK---LLAESGRFSV-SRSGSTSTLTISNVTPEDSGTYTCAATNSSGS 76

                   ....*....
gi 209862949   276 LRADFPLSV 284
Cdd:smart00410  77 ASSGTTLTV 85

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 209862949 361 DVCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22603    1 EDCLLPSETGPCKGSFPRYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 53

Pseudocerastes persicus trypsin inhibitor (PPTI), Kunitz-type serine protease inhibitor bitisilin, and similar proteins; This group contains Pseudocerastes persicus trypsin inhibitor (PPTI), Bitis gabonica Kunitz-type serine protease inhibitor bitisilin-1 (BG-11), -2 (BG-15) and -3 (two-Kunitz protease inhibitor), Oxyuranus scutellatus scutellatus taicatoxin, and serine protease inhibitor component (TSPI, also called venom protease inhibitor 1 or venom protease inhibitor 2), among others. PPTI from P. persicus venom shows inhibitory effect against trypsin proteolytic activity and has similarities to dendrotoxins (DTXs), with corresponding functionally important residues. Studies have shown the ability of PPTI to inhibit voltage-gated potassium channels, and consequently have dual functionality. Bitilisins 1, 2, and 3 are serine protease inhibitors expressed in snake venom glands; bitsilin-3 consists of two Kunitz protease inhibitor domains. Taicatoxin inhibits trypsin, tissue kallikrein, elastase, plasmin and factor Xa, and is also known to block the voltage-dependent L-type calcium channels from the heart, and the small conductance calcium-activated potassium channels (KCa) in chromaffin cells and in the brain. The structures of these Kunitz-type proteins are similar to other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 209862949 363 CALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22608    4 CYLPADPGPCKAYIPRFYYNSASNKCQQFIYGGCKGNANNFETKDECRYTC 54

Kunitz domain of epididymal protease inhibitor eppin and similar proteins; This subfamily includes the Kunitz inhibitor domain protein eppin (also called Cancer/testis antigen 71 or CT71, epididymal protease inhibitor, protease inhibitor WAP7, serine protease inhibitor-like with Kunitz and WAP domains 1, or WAP four-disulfide core domain protein 7) as well as WAP four-disulfide core domain proteins 6A and 6B in mice, and similar proteins. Eppin is a serine protease inhibitor that plays an essential role in male reproduction and fertility. It modulates the hydrolysis of seminal fluid protein semenogelin 1 (SEMG1) by the serine protease kallikrein-related peptidase 3 (KLK3, PSA), provides antimicrobial protection for spermatozoa in the ejaculate coagulum, and binds SEMG1, thereby inhibiting sperm motility. Thus, eppin could potentially be used as a target for male contraception. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 209862949 361 DVCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDACPVPR 417
Cdd:cd22611    1 DVCSLPKESGPCMAYFPRWWYDKETNTCSKFIYGGCQGNNNNFQSEAICQNICKKKR 57

Kunitz-type domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes the Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. HAI-2 Kunitz domain 1 (KD1) has been found to be the domain responsible for inhibition of hepatocyte growth factor (HGF) activator; activated HGF/scatter factor (HGF/SF) binds to its receptor tyrosine kinase MET to induce dimerization and initiate phosphorylation cascades leading to comprehensive cellular changes that, in the deregulated context of cancer, drive malignant transformation and progression. HAI-2 has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer; its loss leads to tumor growth and progression in part due to increased MET signaling. HAI-2 is also a specific substrate for mesotrypsin, which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in HGF/SF activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. The structures of these KD1 domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 209862949 361 DVCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22621    1 DFCHLPKVVGRCRASFPRWWYNATSQSCQEFIFGGCKGNLNNFLSEQECLQKC 53

Kunitz domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 209862949 361 DVCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22617    2 KVCREVPDEGPCRALITRYFYNMTSMRCEEFTYGGCYGNGNNFRDKSSCISAC 54

early lactation protein (ELP), colostrum trypsin inhibitor (CTI), and similar proteins; This model includes the Kunitz-type proteins, colostrum trypsin inhibitor (CTI, also called colostrum BPI) and early lactation protein (ELP). In marsupials, the ELP gene is expressed in the mammary gland and the protein is secreted into milk during early lactation. Mature ELP shares approximately 55.4% similarity with the colostrum-specific bovine CTI protein. Marsupial ELP and eutherian CTI both have a single Kunitz domain and are secreted only during the early lactation phases, suggesting that this protein may have an important role in the immunologically immature young of these species. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 209862949 361 DVCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22632    2 SLCQLPPARGPCRSNILRYFYNSTSRECEPFIYGGCNGNANNFETVEMCLRTC 54

Immunoglobulin domain; The members here are composed of the immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. Members of this group are components of immunoglobulin, neuroglia, cell surface glycoproteins, including T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins, including butyrophilin and chondroitin sulfate proteoglycan core protein. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond. Ig superfamily (IgSF) domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Typically, the V-set domains have A, B, E, and D strands in one sheet and A', G, F, C, C' and C" in the other. The structures in C1-set are smaller than those in the V-set; they have one beta sheet that is formed by strands A, B, E, and D and the other by strands G, F, C, and C'. Moreover, a C1-set Ig domain contains a short C' strand (three residues) and lacks A' and C" strand. Unlike other Ig domain sets, C2-set structures do not have a D strand. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 209862949 207 ASLHCDVSGRPPPAVTWEKQshqreNLIMRPDQMYGNVVVTSIGQLVLYNAQLEDAGLYTCTARNAAG 274
Cdd:cd00096    1 VTLTCSASGNPPPTITWYKN-----GKPLPPSSRDSRRSELGNGTLTISNVTLEDSGTYTCVASNSAG 63

Kunitz-type domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. It has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer, the loss of which leads to tumor growth and progression attributable at least in part to increased MET signaling. HAI-2 is a specific substrate of mesotrypsin which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in hetatocyte growth factor/scatter factor (HGF/SF) activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. KD2 is similar to KD1, whose structure is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 209862949 363 CALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22622    3 CAAPRVTGPCRAAFPRWYYDPESQSCKEFIYGGCRGNKNNYLSEEECMDRC 53

second Kunitz domain of bikunin and similar proteins; This subfamily includes the C-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. Bikunin is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the second repeat.

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                 ....*....|....*....|....*....|....*....|....*....|...
gi 209862949 361 DVCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22597    2 AACRLPIVPGPCKGFVDLWAFDAVQGKCVPFSYGGCQGNGNKFYSEKECEEYC 54

first Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the first repeat.

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                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 209862949 362 VCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDACPVPR 417
Cdd:cd22599    5 ICRLPADEGICRALIPRFYFNTETGQCTEFIYGGCGGNENNFETIEECEKACGAPE 60

Immunoglobulin (Ig)-like ectodomain of the LRIG1 (Leucine-rich Repeats And Immunoglobulin-like Domains Protein 1) and similar proteins; member of the I-set of IgSF domains; The members here are composed of subgroup of the immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond. The ectodomain of LRIG1 has two distinct regions: the proposed 15 LRRs and three Ig-like domains closer to the membrane. LRIG1 has been reported to interact with many receptor tyrosine kinases, GDNF/c-Ret, E-cadherin, JAK/STAT, c-Met, and the EGFR family signaling systems. Immunoglobulin Superfamily (IgSF) domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. The structure of the LRIG1 extracellular Ig domain lacks a C" strand and thus is better described as a member of the I-set of IgSF domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 209862949 196 PSPQAVHVGGTASLHCDVSGRPPPAVTWEKQ-------SHQRENLIMRPDQMYgnvvvtsigqlVLYNAQLEDAGLYTCT 268
Cdd:cd05763    6 PHDITIRAGSTARLECAATGHPTPQIAWQKDggtdfpaARERRMHVMPEDDVF-----------FIVDVKIEDTGVYSCT 74

                         90
                 ....*....|....*..
gi 209862949 269 ARNAAGLLRADFPLSVL 285
Cdd:cd05763   75 AQNSAGSISANATLTVL 91

Kunitz protease inhibitor (KPI) domain 3 (KPI-3 or K3) of tissue factor pathway inhibitor (TFPI) and TFPI2, and similar proteins; This model represents the third Kunitz-type domain (K3 or KPI-3) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI), and of TFPI2 (or TFPI-2). TFPI1 down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI1 complex that then slowly isomerizes to a tight FXa-TFPI1* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI1-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI1 consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; while the K1 domain of TFPI has been shown to bind and inhibit FVIIa and the K2 domain similarly inhibits FXa, the K3 domain has no known inhibitory function. However, Protein S, which functions as a cofactor for TFPI to efficiently enhance TFPI inhibition of FXa and FXa activated TF-VIIa, is dependent on direct interactions with two important residues within K3, a Glutamate and an Arginine. This model also includes TFPI2 Kunitz domain 3 (KD3). TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 209862949 363 CALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22615    4 CLSPKDEGLCSASVTRYYYNSATKTCEPFNYTGCGGNNNNFTSKKDCLRVC 54

Kunitz-type domain from the alpha1 chain of type VII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type VII collagen (collagen alpha-1(VII) chain also called long-chain collagen or LC collagen) and similar proteins. LC collagen, encoded by the COL7A1 gene, is a stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen. So far, over 800 COL7A1 mutations have been reported, including missense, nonsense, splicing, insertion, and deletion mutations which to varying degrees leads to deficiency of type VII collagen. Epidermolysis bullosa acquisita (EBA) is an autoimmune acquired blistering skin disease resulting from autoantibodies to type VII collagen. The COL7A1 protein contains a Kunitz domain, the deactivation of which induces tumorigenesis. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 209862949 361 DVCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22627    1 DPCLLPMDEGSCSDYTLLWYYHQKAGECRPFVYGGCGGNANRFSSKEDCELRC 53

first Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the first Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

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                 ....*....|....*....|....*....|....*....|....*....|....
gi 209862949 360 GDVCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22601    1 IDVCDLPADRGPCTAYIPRWFYNKTTKKCEKFVYGGCQGNKNRFETKDDCLANC 54

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 209862949 363 CALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22631    1 CLLGQDAGSCQNYTMMWFFDSKQGRCSRFWYGGCGGNANRFETQEECENLC 51

Stichodactyla helianthus Kunitz inhibitor protein ShPI-1, Heteractis crispa protease inhibitor stichotoxin-Hcr2e, and similar proteins; This model includes Kunitz inhibitor protein ShPI-1, the major protease inhibitor from the sea anemone Stichodactyla helianthus, as well as protease inhibitor stichotoxin-Hcr2e (also called PI- stichotoxin-Hcr2e, PI-SHTX-Hcr2e, or Kunitz-type serine protease inhibitor InhVJ) and HCRG1 from Heteractis crispa. ShPI-1 has an unusually broad specificity toward several serine proteases, including trypsin, chymotrypsin, human neutrophil elastase, kallikrein and plasmin, and can also bind aspartic and cysteine proteases, such as pepsin and papain, respectively. PI-SHTX-Hcr2e and HCRG1 inhibit trypsin and chymotrypsin, but do not inhibit the serine proteases plasmin, thrombin, kallikrein, the cysteine proteinase papain, and the aspartic protease pepsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

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                 ....*....|....*....|....*....|....*....|....*....|..
gi 209862949 362 VCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22618    1 ICSEPKVVGPCKAYFPRFYFDSETGKCTPFIYGGCGGNGNNFETLHACRAIC 52

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

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                 ....*....|....*....|....*....|....*....|....*....|...
gi 209862949 361 DVCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22614    3 DFCFLEEDPGICRGLITRYFYNNQSKQCERFKYGGCLGNQNNFESLEECQNTC 55

Kunitz domain found in the amyloid-beta precursor protein (ABPP) subfamily; This subfamily includes the amyloid-beta precursor protein (ABPP, also called APP, APPI, Alzheimer disease amyloid protein, amyloid-beta A4 protein, cerebral vascular amyloid peptide (CVAP), protease nexin II (PN2)), as well as amyloid-like protein 2 (APLP2, also called amyloid protein homolog or APPH), among others. ABPP/APPI is an inhibitor of serine proteases such as anionic and cationic trypsins. For example, APPI-4M is a variant that specifically inhibits Kallikrein (KLK)-related peptidase 6 (KLK6), which is highly upregulated in several types of cancer where its increased activity promotes cancer invasion and metastasis. Amyloid-like protein 2 (APLP2) inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein, and may play a role in the regulation of hemostasis. Proteins in this subfamily contain a single Kunitz domain, with a structure similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

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                 ....*....|....*....|....*....|....*....|....*....|..
gi 209862949 362 VCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22607    1 VCSEQAETGPCRAMMPRWYFDVTEGKCAPFIYGGCGGNRNNFESEEYCMAVC 52

Immunoglobulin domain; This domain contains immunoglobulin-like domains.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 209862949  194 NSPSPQAVHVGGTASLHCDVSGRPPPAVTWEKqshqrenlimrpdqmyGNVVVTSIGQLVLYNAQLEDAGLYTCTARNAA 273
Cdd:pfam13895   4 LTPSPTVVTEGEPVTLTCSAPGNPPPSYTWYK----------------DGSAISSSPNFFTLSVSAEDSGTYTCVARNGR 67

                          90
                  ....*....|..
gi 209862949  274 G-LLRADFPLSV 284
Cdd:pfam13895  68 GgKVSNPVELTV 79

first Kunitz domain of bikunin and similar proteins; This subfamily includes the N-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. It is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the first repeat.

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                 ....*....|....*....|....*....|....*....|....*....|...
gi 209862949 361 DVCALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22596    1 DSCKLPPDAGPCFGMIQRYFYNSSSMACQTFNYGGCLGNQNNFVTEKECLQTC 53

Fifth Ig-like domain of Roundabout (Robo) homolog 1/2, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fifth Ig-like domain of Roundabout (Robo) homolog 1/2 and similar domains. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, -2, and -3), and three mammalian Slit homologs (Slit-1,-2, -3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, -2, and -3 are expressed by commissural neurons in the vertebrate spinal cord and Slits 1, -2, -3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of slit responsiveness, antagonizes slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be is the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. The fifth Ig-like domain of Robo 1 and 2 is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand but lack a C" strand. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 209862949 195 SPSPQAVHVGGTASLHCDVSGRPPPAVTWEKQSHQrenlIMRPDQmygNVVVTSIGQLVLYNAQLEDAGLYTCTARNAAG 274
Cdd:cd20952    5 GPQNQTVAVGGTVVLNCQATGEPVPTISWLKDGVP----LLGKDE---RITTLENGSLQIKGAEKSDTGEYTCVALNLSG 77

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

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                 ....*....|....*....|....*....|....*....|....*....|.
gi 209862949 363 CALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22639    1 CSLPKDRGPCRNYTVKWYFDMAYGGCSRFWYGGCGGNGNRFDTEEECKAVC 51

trophoblast Kunitz domain protein (TKDP) and similar proteins; This model contains the trophoblast Kunitz domain protein 1 (TKDP-1) and splice variant TKDP-4, among others, which are Kunitz inhibitor domain proteins. TKDP-1 is expressed in the trophectoderm which forms the outer epithelial layer of the trophoblast, and may play a role in mediating maternal-conceptus interactions in the immediate preimplantation period. However, it does not appear to have proteinase inhibitory activity. These domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

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                 ....*....|....*....|....*....|....*....|....*....|.
gi 209862949 363 CALPPVQGPCQGWEPRWAYSPLLQQCHPFIYSGCEGNSNNFESRESCEDAC 413
Cdd:cd22609    2 CLEPKVVGVCKASMTRYFYNAQTGHCEQFVYGGCGGNRNNFLTLEDCMKTC 52