Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionUniProtKB
Protein C inhibitor (PCI) is a heparin-dependent serpin present in a native form in plasma at concentrations of 5 micrograms/mL. In vitro, PCI inhibits activated protein C (APC), thrombin, plasma kallikrein (KK) and urokinase-(uPA) and tissue-type plasminogen activator (tPA), and we have shown in vivo inhibition of APC, uPA and KK by PCI. In order to further characterize the physiological role of PCI, we have measured the level of PCI in several biological fluids. PCI antigen was assayed by ELISA and PCI activity was measured by its capability to form complexes with APC in the presence of heparin. Seminal plasma from voluntary donors had PCI levels (160 +/- 20 micrograms/mL, mean +/- SD) about 30 or 40 times higher than those found in blood plasma. Patients under a fertilization program had significantly reduced PCI seminal levels (110 +/- 35 micrograms/mL). Seminal plasma PCI retained about 45% of its activity immediately after ejaculation, and the activity rapidly decreased following incubation of seminal plasma at 37 degrees C, in parallel with the appearance of complexes of PCI with prostate-specific antigen (PSA). PCI was present in seminal vesicle secretion, obtained by autopsy, at concentration similar to that observed in semen, was mostly active and was not inactivated by incubation of secretion at 37 degrees C. The mean functional and antigen levels of PCI in urine from normal donors were 0.58 and 0.25 micrograms/mL, respectively, whereas in saliva these levels were 20 and 0.8 ng/mL, respectively. Amniotic fluid contained PCI antigen levels of 2.1 +/- 0.2 microgram/mL. These results show that PCI is secreted in the seminal vesicles in a functional form, and suggest that PSA, a major secretory component of the prostate, is responsible for its inactivation. They also suggest a physiological role of PCI in reproduction, and show that PCI is present in various biological fluids.
Catalysis of the hydrolysis of internal, alpha-peptide bonds in a polypeptide chain by a catalytic mechanism that involves a catalytic triad consisting of a serine nucleophile that is activated by a proton relay involving an acidic residue (e.g. aspartate or glutamate) and a basic residue (usually histidine).
Catalysis of the hydrolysis of peptide bonds in a polypeptide chain by a catalytic mechanism that involves a catalytic triad consisting of a serine nucleophile that is activated by a proton relay involving an acidic residue (e.g. aspartate or glutamate) and a basic residue (usually histidine).
The amino acid sequence of human prostate-specific antigen (APS) suggests that it is a member of the glandular kallikrein subfamily of serine proteases. In the mouse, the kallikrein-like family is localized in a single locus on chromosome 7, while other serine proteases are distributed over a variety of different chromosomes. To investigate the physical relationship between the human kallikrein genes, we have used in situ hybridization and Southern analysis of a human x mouse somatic cell hybrid panel to map the APS gene to 19q13, concordant with the renal kallikrein KLK1 gene. This finding indicates that APS is a member of a human kallikrein-like gene family with analogous organization to that of the mouse.
The traditional human kallikrein gene family consists of three genes, namely KLK1 [encoding human kallikrein 1 (hK1) or pancreatic/renal kallikrein], KLK2 (encoding hK2, previously known as human glandular kallikrein 1) and KLK3 [encoding hK3 or prostate-specific antigen (PSA)]. KLK2 and KLK3 have important applications in prostate cancer diagnostics and, more recently, in breast cancer diagnostics. During the past two to three years, new putative members of the human kallikrein gene family have been identified, including the PRSSL1 gene [encoding normal epithelial cell-specific 1 gene (NES1)], the gene encoding zyme/protease M/neurosin, the gene encoding prostase/KLK-L1, and the genes encoding neuropsin, stratum corneum chymotryptic enzyme and trypsin-like serine protease. Another five putative kallikrein genes, provisionally named KLK-L2, KLK-L3, KLK-L4, KLK-L5 and KLK-L6, have also been identified. Many of the newly identified kallikrein-like genes are regulated by steroid hormones, and a few kallikreins (NES1, protease M, PSA) are known to be downregulated in breast and possibly other cancers. NES1 appears to be a novel breast cancer tumor suppressor protein and PSA a potent inhibitor of angiogenesis. This brief review summarizes recent developments and possible applications of the newly defined and expanded human kallikrein gene locus.
Inhibited by SERPINA5. Activity is strongly inhibited by Zn2+, 100 times more abundant in semen than in serum. This inhibition is relieved by exposure to semenogelins, which are avid zinc binders.
Protein C inhibitor (PCI) is a heparin-dependent serpin present in a native form in plasma at concentrations of 5 micrograms/mL. In vitro, PCI inhibits activated protein C (APC), thrombin, plasma kallikrein (KK) and urokinase-(uPA) and tissue-type plasminogen activator (tPA), and we have shown in vivo inhibition of APC, uPA and KK by PCI. In order to further characterize the physiological role of PCI, we have measured the level of PCI in several biological fluids. PCI antigen was assayed by ELISA and PCI activity was measured by its capability to form complexes with APC in the presence of heparin. Seminal plasma from voluntary donors had PCI levels (160 +/- 20 micrograms/mL, mean +/- SD) about 30 or 40 times higher than those found in blood plasma. Patients under a fertilization program had significantly reduced PCI seminal levels (110 +/- 35 micrograms/mL). Seminal plasma PCI retained about 45% of its activity immediately after ejaculation, and the activity rapidly decreased following incubation of seminal plasma at 37 degrees C, in parallel with the appearance of complexes of PCI with prostate-specific antigen (PSA). PCI was present in seminal vesicle secretion, obtained by autopsy, at concentration similar to that observed in semen, was mostly active and was not inactivated by incubation of secretion at 37 degrees C. The mean functional and antigen levels of PCI in urine from normal donors were 0.58 and 0.25 micrograms/mL, respectively, whereas in saliva these levels were 20 and 0.8 ng/mL, respectively. Amniotic fluid contained PCI antigen levels of 2.1 +/- 0.2 microgram/mL. These results show that PCI is secreted in the seminal vesicles in a functional form, and suggest that PSA, a major secretory component of the prostate, is responsible for its inactivation. They also suggest a physiological role of PCI in reproduction, and show that PCI is present in various biological fluids.
Human prostate-specific antigen (PSA or KLK3) is an important marker for the diagnosis and management of prostate cancer. This is an androgen-regulated glycoprotein of the kallikrein-related protease family secreted by prostatic epithelial cells. Its physiological function is to cleave semenogelins in the seminal coagulum and its enzymatic activity is strongly modulated by zinc ions. Here we present the first crystal structure of human PSA in complex with monoclonal antibody (mAb) 8G8F5 that enhances its enzymatic activity. The mAb recognizes an epitope composed of five discontinuous segments including residues from the kallikrein loop and stabilizes PSA in an "open and active conformation" that accelerates catalysis. We also present the crystal structure of PSA in complex with both the mAb 8G8F5 and a fluorogenic substrate Mu-KGISSQY-AFC, derived from semenogelin I. By exploiting the inhibition of PSA by zinc ions, we were able to obtain a substrate acyl intermediate covalently linked to the catalytic serine, at pH 7.3 but not at pH 5.5. Moreover, the inhibition of PSA activity by zinc was found to be modulated by pH variations but not by the antibody binding. The correlation of the different data with the physiological conditions under which PSA can cleave semenogelins is discussed.
Enzyme which catalyzes hydrolysis reaction, i.e. the addition of the hydrogen and hydroxyl ions of water to a molecule with its consequent splitting into two or more simpler molecules.
Proteolytic enzyme with a serine residue (Ser) in its active site. The reactivity of the serine residue is ensured by the vicinity of a histidine and an aspartate residue (catalytic triad), all three residues are required for the charge relay system to take place.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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