Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. 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 25149822 1376 CDEAKDTGPCTNFVTKWYYNKADGTCNRFHYGGCQGTNNRFDNEQQCKAAC 1426
Cdd:cd22637    1 CDQPKDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 25149822 1433 CQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:cd00109    1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

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 25149822   1149 RCYLPRVDGPlrCDQLQPRYYYDHSKKHCVAFWWRGCLGNANNFNSFEECSMFCK 1203
Cdd:pfam00014    1 ICSLPPDSGP--CKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTCR 53

ADAMTS cysteine-rich domain; This cysteine rich domain is found in a variety of ADAMTS and ADAMTS-like endopeptidases widely spread in animals. It is a well-conserved cysteine-rich sequence containing 10 cysteine residues. ADAM-TS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) is closely related to the ADAM family (A Disintegrin and Metalloproteinase, pfam08516) and consists of at least 20 members sharing a high degree of sequence similarity and conserved domain organization. Members of the ADAMTS family have been implicated in a range of diseases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 25149822    127 DFRAEQCSKFNDEAL-----DGNYHKW---TPY-KGKNKCELVCKPESGNFYYKWADKVVDGTKC------DSKSNDICV 191
Cdd:pfam19236    4 EFMSQQCARTDGQPLrsspgGASFYHWgaaVPHsQGDALCRHMCRAIGESFIMKRGDSFLDGTRCmpsgprEDGTLSLCV 83

                           90       100       110
                   ....*....|....*....|....*....|..
gi 25149822    192 DGECLPVGCDGKLGSSLKFDKCGKCDGDGSTC 223
Cdd:pfam19236   84 LGSCRTFGCDGRMDSQQVWDRCQVCGGDNSTC 115

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 25149822    465 WQAGPWSACSEKCGDAFQYRSVTCRSEKEGEegkLLAADACPAdeQEKFDTERTCNLGPC 524
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGS---IVPDSECSA--QKKPPETQSCNLKPC 55

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 25149822      79 WGPWVPENECSRSCGGGVQLEKRQCS--------GDCTGASVRYISCNLNACE 123
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCspppqnggGPCTGEDVETRACNEQPCP 53

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. 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 25149822 1376 CDEAKDTGPCTNFVTKWYYNKADGTCNRFHYGGCQGTNNRFDNEQQCKAAC 1426
Cdd:cd22637    1 CDQPKDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 25149822 1433 CQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:cd00109    1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

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 25149822   1432 ACQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:pfam00014    1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTC 52

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 25149822    1431 DACQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:smart00131    1 DVCLLPPDTGPCGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 25149822    1374 SVCDEAKDTGPCTNFVTKWYYNKADGTCNRFHYGGCQGTNNRFDNEQQCKAAC 1426
Cdd:smart00131    1 DVCLLPPDTGPCGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 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 25149822   1149 RCYLPRVDGPlrCDQLQPRYYYDHSKKHCVAFWWRGCLGNANNFNSFEECSMFCK 1203
Cdd:pfam00014    1 ICSLPPDSGP--CKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTCR 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 25149822   1088 ACNQTQESGTvcGAGYKLAWHYDTTEGRCNQFWYGGCGGNDNNFASQDMCETICV 1142
Cdd:pfam00014    1 ICSLPPDSGP--CKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTCR 53

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....
gi 25149822    1088 ACNQTQESGTvCGaGYKLAWHYDTTEGRCNQFWYGGCGGNDNNFASQDMCETIC 1141
Cdd:smart00131    2 VCLLPPDTGP-CG-GSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

ADAMTS cysteine-rich domain; This cysteine rich domain is found in a variety of ADAMTS and ADAMTS-like endopeptidases widely spread in animals. It is a well-conserved cysteine-rich sequence containing 10 cysteine residues. ADAM-TS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) is closely related to the ADAM family (A Disintegrin and Metalloproteinase, pfam08516) and consists of at least 20 members sharing a high degree of sequence similarity and conserved domain organization. Members of the ADAMTS family have been implicated in a range of diseases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 25149822    127 DFRAEQCSKFNDEAL-----DGNYHKW---TPY-KGKNKCELVCKPESGNFYYKWADKVVDGTKC------DSKSNDICV 191
Cdd:pfam19236    4 EFMSQQCARTDGQPLrsspgGASFYHWgaaVPHsQGDALCRHMCRAIGESFIMKRGDSFLDGTRCmpsgprEDGTLSLCV 83

                           90       100       110
                   ....*....|....*....|....*....|..
gi 25149822    192 DGECLPVGCDGKLGSSLKFDKCGKCDGDGSTC 223
Cdd:pfam19236   84 LGSCRTFGCDGRMDSQQVWDRCQVCGGDNSTC 115

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 25149822    465 WQAGPWSACSEKCGDAFQYRSVTCRSEKEGEegkLLAADACPAdeQEKFDTERTCNLGPC 524
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGS---IVPDSECSA--QKKPPETQSCNLKPC 55

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 25149822      79 WGPWVPENECSRSCGGGVQLEKRQCS--------GDCTGASVRYISCNLNACE 123
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCspppqnggGPCTGEDVETRACNEQPCP 53

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 25149822    589 WTVSEWSKCTTECGHGHKTRRVICaIHQNGGLEVVDEGHCQAEKPEGKTNCtNEEKC 645
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQC-VQKGGGSIVPDSECSAQKKPPETQSC-NLKPC 55

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*...
gi 25149822     468 GPWSACSEKCGDAFQYRSVTCRSEKEGEEGKLlaadaCPADEQEKfdteRTCNLGPCE 525
Cdd:smart00209    5 SEWSPCSVTCGGGVQTRTRSCCSPPPQNGGGP-----CTGEDVET----RACNEQPCP 53

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. 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 25149822 1376 CDEAKDTGPCTNFVTKWYYNKADGTCNRFHYGGCQGTNNRFDNEQQCKAAC 1426
Cdd:cd22637    1 CDQPKDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 25149822 1433 CQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:cd00109    1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

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 25149822   1432 ACQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:pfam00014    1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTC 52

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 25149822    1431 DACQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:smart00131    1 DVCLLPPDTGPCGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 25149822 1431 DACQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:cd22596    1 DSCKLPPDAGPCFGMIQRYFYNSSSMACQTFNYGGCLGNQNNFVTEKECLQTC 53

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 25149822 1271 CRSRQDAGPCETYSDQWFYNAFSQECETFTYGGCGGNLNRFRSKDECEQRC 1321
Cdd:cd00109    1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

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 25149822   1149 RCYLPRVDGPlrCDQLQPRYYYDHSKKHCVAFWWRGCLGNANNFNSFEECSMFCK 1203
Cdd:pfam00014    1 ICSLPPDSGP--CKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTCR 53

Kunitz-type domain from the alpha1 chain of type XXVIII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type XXVIII collagen (collagen alpha-1(XXVIII) chain) and similar proteins. The zebrafish has four collagen XXVIII genes all of which are differentially expressed in the liver, thymus, muscle, intestine and skin; only the alpha1 chain contains the Kunitz domain which is often proteolytically processed. Mammals only contain the alpha1 collagen chain, expressed mostly in dorsal root ganglia and peripheral nerves. The Kunitz domain is found at the C-terminus, and is most related to Kunitz domains of papilin and alpha3(VI) collagen. 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 25149822 1376 CDEAKDTGPCTNFVTKWYYNKADGTCNRFHYGGCQGTNNRFDNEQQCKAAC 1426
Cdd:cd22628    1 CLEPLDPGPCREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. 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 25149822 1376 CDEAKDTG-PCTNFVTKWYYNKADGTCNRFHYGGCQGTNNRFDNEQQCKAAC 1426
Cdd:cd22635    1 CLLDKDAGtVCGDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

venom Kunitz-type proteins such as textilinin, BF9 and PILP; This group includes toxins isolated from snake venoms, such as textilinin, vestiginin, spermatin, mulgin, venom basic protease inhibitor IX (BF9), and protease inhibitor-like protein (PILP), among others. Pseudonaja textilis textilinin-1 is a Kunitz-type serine protease inhibitor that binds to and blocks the activity of a range of serine proteases, including plasmin and trypsin. Ability of testilinin to inhibit plasmin, a protease involved in fibrinolysis, raises the possibility that it may be used as an alternative to aprotinin (Trasylol), which is a systemic antibleeding agent in surgery. Also included is the Bungarus fasciatus fraction IX (BF9), a chymotrypsin inhibitor that binds chymotrypsin but not trypsin. Protease inhibitor-like proteins PILP-1 and PILP-2 show weak binding and inhibition of matrix metalloproteinase-2 (MMP-2) and show an activity in inhibiting migration and invasion of neuroblastoma; they do not inhibit chymotrypsin or trypsin. The structures of these toxins 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 25149822 1433 CQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:cd22594    5 CELPADPGPCNAYKPAFYYNPASHKCLEFIYGGCGGNANNFKTIDECHRTC 55

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.

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                   ....*....|....*....|....*....|....*....|....*....|....*
gi 25149822   1088 ACNQTQESGTvcGAGYKLAWHYDTTEGRCNQFWYGGCGGNDNNFASQDMCETICV 1142
Cdd:pfam00014    1 ICSLPPDSGP--CKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTCR 53

Kunitz-type domain from the alpha6 chain of human 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), encoded by COL6A6 gene, 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.

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                 ....*....|....*....|....*....|....*....|....*....|..
gi 25149822 1375 VCDEAKDTGPCTNFVTKWYYNKADGTCNRFHYGGCQGTNNRFDNEQQCKAAC 1426
Cdd:cd22630    2 ACSLDQDEGECQNYVLKWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALC 53

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

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                 ....*....|....*....|....*....|....*....|....*....|...
gi 25149822 1150 CYLPRVDGPlrCDQLQPRYYYDHSKKHCVAFWWRGCLGNANNFNSFEECSMFC 1202
Cdd:cd00109    1 CLLPPDPGP--CRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

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 25149822 1431 DACQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:cd22614    3 DFCFLEEDPGICRGLITRYFYNNQSKQCERFKYGGCLGNQNNFESLEECQNTC 55

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. 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. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. 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.

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                 ....*....|....*....|....*....|....*....|....*....|...
gi 25149822 1089 CNQTQESGTvCGaGYKLAWHYDTTEGRCNQFWYGGCGGNDNNFASQDMCETIC 1141
Cdd:cd22629    3 CKLPKDEGT-CR-DFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53

Kunitz protease inhibitor (KPI) domain 1 (KPI-1 or K1) of tissue factor pathway inhibitor (TFPI); This model represents the first Kunitz-type domain (K1 or KPI-1) 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 K1 domain of TFPI has been shown to bind and inhibit FVIIa while the K2 domain similarly inhibits FXa. Small peptide blocking inhibition of FXa and TF-FVIIa by TFPI shows that domain K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. The structure of the K1 domain is 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 25149822 1433 CQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:cd22613    4 CAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNENRFETLEECKKTC 54

dendrotoxins I, K, B and similar proteins; This group includes toxins isolated from snake venoms, such as dendrotoxins (DTXs) I, K and B, mambaquaretin-1 (MQ-1) and calcicludine. The dendrotoxins have little or no anti-protease activity but have been shown to block certain subtypes of voltage dependent potassium channels in neurons. Dendroaspis angusticeps (green mamba) alpha-dendrotoxin is a neurotoxin that enhances acetylcholine release at neuromuscular junctions. Studies with cloned K(+) channels show that this toxin blocks Kv1.1, Kv1.2 and Kv1.6 channels in the nanomolar range, whereas Dendroaspis polylepis (black mamba) dendrotoxin K preferentially blocks Kv1.1 channels. Also, structural analogs of dendrotoxins have facilitated defining the molecular recognition properties of different types of K(+) channels, and therefore, dendrotoxins are widely used as probes for studying the function of K(+) channels in physiology and pathophysiology. 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.

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                 ....*....|....*....|....*....|....*....|....*....|..
gi 25149822 1432 ACQLPKVQGPCSGKHSYYYYNTASHQCETFTYGGCLGNTNRFATIEECQARC 1483
Cdd:cd22595    3 FCKLPVRPGPCKAFISAFYYNWKAKKCHPFTYSGCGGNANRFKTIEECRRTC 54

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

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                    ....*....|....*....|....*....|....*....|....*....|....
gi 25149822    1088 ACNQTQESGTvCGaGYKLAWHYDTTEGRCNQFWYGGCGGNDNNFASQDMCETIC 1141
Cdd:smart00131    2 VCLLPPDTGP-CG-GSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

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.

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                 ....*....|....*....|....*....|....*....|....*....|...
gi 25149822 1269 DICRSRQDAGPCETYSDQWFYNAFSQECETFTYGGCGGNLNRFRSKDECEQRC 1321
Cdd:cd22627    1 DPCLLPMDEGSCSDYTLLWYYHQKAGECRPFVYGGCGGNANRFSSKEDCELRC 53

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 25149822 1269 DICRSRQDAGPCETYSDQWFYNAFSQECETFTYGGCGGNLNRFRSKDECEQRC 1321
Cdd:cd22596    1 DSCKLPPDAGPCFGMIQRYFYNSSSMACQTFNYGGCLGNQNNFVTEKECLQTC 53

Kunitz protease inhibitor (KPI) domain 1 (KPI-1 or K1) of tissue factor pathway inhibitor (TFPI); This model represents the first Kunitz-type domain (K1 or KPI-1) 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 K1 domain of TFPI has been shown to bind and inhibit FVIIa while the K2 domain similarly inhibits FXa. Small peptide blocking inhibition of FXa and TF-FVIIa by TFPI shows that domain K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. The structure of the K1 domain is 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 25149822 1270 ICRSRQDAGPCETYSDQWFYNAFSQECETFTYGGCGGNLNRFRSKDECEQRC 1321
Cdd:cd22613    3 FCAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNENRFETLEECKKTC 54

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) 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. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 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. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen 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 25149822 1269 DICRSRQDAGPCETYSDQWFYNAFSQECETFTYGGCGGNLNRFRSKDECEQRC 1321
Cdd:cd22616    3 EICLLPPDEGPCRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) 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. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 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. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen 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.

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                 ....*....|....*....|....*....|....*....|....*....|...
gi 25149822 1150 CYLPRVDGPlrCDQLQPRYYYDHSKKHCVAFWWRGCLGNANNFNSFEECSMFC 1202
Cdd:cd22616    5 CLLPPDEGP--CRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55