Plasma protease inhibitors in mouse and man: divergence within the reactive centre regions

Hill, Robert E.; Shaw, Phillip; Boyd, Patricia A.; Hastie, Nicholas D.

doi:10.1038/311175a0

Cited by 130 publications

(65 citation statements)

References 26 publications

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“…Differences in active-site P1 residues among several species have been suggested as evidence for evolutionary divergence of ACT-like genes (13,14).…”

Section: Experimental Procedures and Materialsmentioning

confidence: 99%

“…This result appears consistent with the finding of two isoforms of bovine liver ACTs that may be encoded by separate genes. In other species, mouse (13) and rat (14) ACT-related cDNAs (known as contrapsins) are multicopy genes that encode isoforms of these serpins. However, human ACT exists as a single or two-copy gene (unpublished data from ref.…”

Section: Experimental Procedures and Materialsmentioning

confidence: 99%

“…The Pi-Pi' residues of bovine ACTs (Ser-Ser and ile-Ser), human ACT (Leu-Ser), and human al-AT (Met-Ser) show differences in PI residues, but all possess serine as P1' residue. Mouse contrapsin, on the other hand, differs in both P1 and P1' residues because it contains Lys-Ala at its reactive site (13). Genomic Blot.…”

Section: Experimental Procedures and Materialsmentioning

confidence: 99%

“…To define the relationship of the primary structure of bovine ACT with human ACT (9, 12), as well as with rodent serpins (13,14), molecular cloning of bovine liver ACT was undertaken. A nearly full-length bovine liver ACT cDNA was obtained, which is predicted to encode the complete primary sequence of ACT.…”

Section: Introductionmentioning

confidence: 99%

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Molecular cloning reveals isoforms of bovine alpha 1-antichymotrypsin.

Hwang¹,

Kohn²,

Hook³

1994

Proc. Natl. Acad. Sci. U.S.A.

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Comparison of bovine a1-antichymotrypsin (ACT) protease inhibitor with that in human was achieved by cloning a nearly full-length bovine ACT cDNA of 1.5 kb, obtained by screening a bovine liver cDNA library with the human liver ACT cDNA. The deduced primary sequence indicated that the 1456-bp bovine ACT cDNA encodes a protein of 416 amino acids that contains the predicted full-length ACT with a 26-residue NH2-terminal signal sequence. Overall, the primary sequence of bovine ACT possesses a high degree of homology (55%) with hman ACT; both bovine and human ACTs share common sequences in the reactive-site domains. Importantly, the reactive site ofbovine ACT poses serine as the predicted P1 position (residue at the NH2-terminal side of the cleaved peptide bond) of the reactive site, whereas human ACT contains leucine in the Pi position. Interestingly, further evidence for heterogeneity in Pi residues was provided by a second partial 0.9-kb bovine liver ACT cDNA done (pHHK11) that contains isoleucine as Pi residue and shares only partial homology (68%) with the deduced primary sequence of the full-length bovine liver ACT cDNA clone (pHHK12). These findings suggest that isoforms of ACT in bovine liver vary in reactive-site P1 residues; the Pi position of the reactive site is often involved in proteae inhibitor speciflcity. Consistent with the hypothesis of ACT isoforms was the demonstration of multiple copies of the bovine ACT gene by genomic blots.a1-Antichymotrypsin (ACT) is a member of the sMrine protease inhibitor family known as serpins. ACT, al-antitrypsin (a1-AT), and antithrombin III are plasma protease inhibitors that represent =10% of total human plasma proteins; these protease inhibitors are related to a variety of diseases (1, 2).The target substrates of ACT are believed to include chymotrypsin-like proteases and neutrophil cathepsin G. Plasma levels of ACT increase by four times in response to inflammatory states (1, 2). Thus, ACT has been implicated in acute-phase responses to burn injuries (3), surgery (4), and certain cancers (5). ACT also binds DNA and inhibits DNA polymerase (6). ACT has been implicated in nervous system functions, as indicated by its colocalization with -3-amyloid peptide in amyloid plaques of Alzheimer disease brains (7). Recent studies have demonstrated a functional role for ACT inhibition of a neuropeptide precursor processing enzyme, "prohormone thiol protease," required in peptide hormone and neurotransmitter biosynthesis (8). These studies implicate the diverse functions of ACT.The specificity of ACT and other serpins in inhibiting target proteases is, in part, determined by the P1 residue at the reactive site that resembles the substrate-cleavage site oftheprotease (1,2), where P1 and P1' represent residues at the NH2-and COOH-terninal sides of the cleaved peptide bond, respectively. Mutagenesis studies (9) have shown that ACT inhibits chymotrypsin when the P1 residue is leucine or methionine; however, ACT with arginine in the P1 position possesses an altered specifi...

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“…Differences in active-site P1 residues among several species have been suggested as evidence for evolutionary divergence of ACT-like genes (13,14).…”

Section: Experimental Procedures and Materialsmentioning

confidence: 99%

Section: Experimental Procedures and Materialsmentioning

confidence: 99%

Section: Experimental Procedures and Materialsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Molecular cloning reveals isoforms of bovine alpha 1-antichymotrypsin.

Hwang¹,

Kohn²,

Hook³

1994

Proc. Natl. Acad. Sci. U.S.A.

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“…The proteins that showed the greatest similarity to the 38-kDa protein were those belonging to a proposed superfamily of proteins, each related to the extent of -30% sequence identity. Several members of this family are plasma proteins that are inhibitors of serine proteases; these include human antithrombin III (22), human a1-antichymotrypsin (23), mouse and human a1-proteinase inhibitor (22,24), human heparin cofactor II (25), baboon a1-antitrypsin (26), and mouse contrapsin (24). Fig.…”

Section: G D Y S N M C N S D V S V D a M I B K T Y I D V N E E Y T E mentioning

confidence: 99%

Hemorrhage in lesions caused by cowpox virus is induced by a viral protein that is related to plasma protein inhibitors of serine proteases.

Pickup¹,

Ink²,

Hu³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

174

110

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Several recombinant cowpox viruses were constructed and used to identify a viral gene that controls the production of hemorrhage in lesions caused by the Brighton Red strain of cowpox virus (CPV-BR). This gene is located in the KpnD fragment of CPV-BR DNA, between 31 and 32 kilobases from the end of the genome. This position corresponds well with that predicted from analyses of the DNA structures of spontaneously generated deletion mutants. The gene responsible for hemorrhage encodes a 38-kDa protein that is one of the most abundant early gene products. The 11-basepair sequence GAAAATATATT present 84 base pairs upstream of its coding region is also present upstream of three other early genes of vaccinia virus; therefore, this sequence may be involved in the regulation of transcription. There is extensive similarity between the predicted amino acid sequence of the 38-kDa protein and the amino acid sequences of several plasma proteins that are inhibitors of various serine proteases involved in blood coagulation pathways. This suggests that the viral protein may possess a similar biological activity, which may enable it to effect hemorrhage by inhibiting one or more of the serine proteases involved in the host's normal processes of blood coagulation and wound containment.The inoculation of cowpox virus (CPV) into the skin of various mammals (guinea pigs, rabbits, humans) results in lesions that exhibit edema, hypertrophy ofthe epidermis, and hemorrhage. Similar effects are produced in CPV lesions (pocks) in the chorioallantoic membrane of developing chicken embryos; there is extensive proliferation of ectodermal and mesodermal cells, edema, and localized hemorrhage that gives the pocks a deep red color (1).CPV variants that do not produce hemorrhage have been isolated from the white pocks that usually comprise up to 1% of the pocks present on chorioallantoic membranes infected with wild-type CPV (2, 3). The existence of these white-pock variants demonstrates that a viral function controls the production of the hemorrhage.Studies of the structures of the DNAs of these white-pock variants have shown that their genomes are generated from the genome of the wild-type virus by large deletions and duplications of sequences (4, 5). Similar results have been obtained from studies of the DNAs of white-pock variants of rabbitpox virus and monkeypox virus (6-8). The rearrangements of DNA that generate the white-pock variants of CPV typically involve the replacement of up to 39 kilobases (kb) of one end of the genome with an inverted copy of up to 50 kb of DNA from the other end (4, 5). The mechanisms by which these rearrangements proceed are unknown; but it is clear that there are no identifiable homologous sequence elements at the sites of the duplication/deletion end points (5). This result suggests that it is the location of essential genes rather than DNA sequence content that limits where rearrangements may occur. The position ofgenes that encode markers, such as production of hemorrhage, will place a further cons...

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Cloning and characterization of the α1-antichymotrypsin produced by human prostate tissue

Lilja

Cockett

et al. 1998

Prostate

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BACKGROUND α1‐antichymotrypsin (ACT) forms stable complexes with prostate‐specific antigen (PSA), a serine protease, and this complex is the major form of PSA in the blood circulation. α1‐antichymotrypsin occurs in the blood in approximately 105 molar excess to PSA, mainly due to hepatic production, but local prostatic production of ACT has been demonstrated by immunohistochemistry and in situ hybridization. The present study was performed to further characterize this prostate‐produced ACT. METHODS The nucleotide structure of the prostatic transcript was determined from ACT coding clones isolated from prostatic cDNA. The occurrence of a prostatic ACT transcript was analyzed by Northern blot. RT‐PCR was used to detect ACT transcripts in cultured prostatic cancer cells. RESULTS Screening of two prostatic cDNA libraries showed the frequency of ACT transcripts to be about 1 clone in 40,000. The cDNA sequence of prostatic ACT is identical to that of the previously published hepatic ACT. Northern blot analysis of mRNA extracted from prostatic tissue showed a single transcript of approximately 1.5 kb. RT‐PCR analysis demonstrated an ACT transcript in cultured prostatic cancer cells. CONCLUSIONS In this study we provide further evidence for a local, prostatic production of ACT. The cDNA sequence data suggest that the peptide backbone of prostatic ACT is identical to the protein derived from the liver, and thus may be functional as a protease inhibitor. Prostate 34:155–161, 1998.© 1998 Wiley‐Liss, Inc.

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Plasma protease inhibitors in mouse and man: divergence within the reactive centre regions

Cited by 130 publications

References 26 publications

Molecular cloning reveals isoforms of bovine alpha 1-antichymotrypsin.

Molecular cloning reveals isoforms of bovine alpha 1-antichymotrypsin.

Hemorrhage in lesions caused by cowpox virus is induced by a viral protein that is related to plasma protein inhibitors of serine proteases.

Cloning and characterization of the α1-antichymotrypsin produced by human prostate tissue

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