Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An exciting application of protein engineering is the creation of proteins with novel functions by the retrofitting of native proteins. Such attempts might be facilitated by the idea of a mosaic architecture of proteins out of structural units. Even though numerous theoretical concepts deal with the delineation of structural "modules," their potential in the design of proteins has not yet been sufficiently exploited. To address this question we used a gain of function approach by designing modular chimeric molecules out of two structurally homologous but functionally diverse members of the superfamily of serine-proteinase inhibitors, alpha1-proteinase inhibitor and thyroxine-binding globulin. Substitution of two of four alpha1-proteinase inhibitor modules (Lys222 to Leu288 and Pro362 to Lys394, respectively), identified by alpha-backbone distance analysis, with their thyroxine-binding globulin homologues resulted in a bifunctional chimera with inhibition of human leukocyte elastase and high affinity thyroxine binding. To our knowledge, this is the first report on a bifunctional chimera engineered from modules of homologous globular proteins. Our results demonstrate how a modular concept can facilitate the design of new functional proteins by swapping structural units chosen from members of a protein superfamily.
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PMID:Modularity of serpins. A bifunctional chimera possessing alpha1-proteinase inhibitor and thyroxine-binding globulin properties. 1032 8

Thyroxine-binding globulin (TBG) is a noninhibitory member of the serine protease inhibitor (serpin) superfamily. A characteristic serpin cleavage product of TBG has been demonstrated in sera of septic patients. We find that a similar cleavage product appears in serum during the rapid decline of immunoassayable TBG and thyroxine (T(4)) that is associated with the inflammatory response to cardiopulmonary bypass (CPB). In vitro cleavage of TBG by the serine protease, neutrophil elastase induces a conformational change that has previously been shown to weaken affinity for T(4.) In vitro protease cleavage also decreases immunoassayable TBG, probably because the conformational change decreases the availability of the TBG epitopes to the measuring antibody. Thus, the rapid decrease in immunoassayable TBG concentration previously attributed to accelerated clearance is caused in part by the proteolytic cleavage per se. The evidence for proteolysis of TBG concurrent with the decrease in serum T(4) during CPB is consistent with the proposed release of T(4) from TBG to cells showing serine protease activity.
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PMID:Cleavage of thyroxine-binding globulin during cardiopulmonary bypass. 1155 48

T(4)-binding globulin (TBG) serves to maintain an important serum pool of thyroid hormones and to prevent their excessive loss in urine. TBG has also been implicated in the tissue distribution and targeted delivery of the hormones, the mechanisms of which remain unclear. By virtue of sequence homology, TBG belongs to the serine proteinase inhibitors superfamily of proteins that are characterized by a reactive site loop serving as a recognition site for serine proteinases. However, both TBG and another serpin with hormone transport function, corticosteroid-binding globulin, are noninhibitory. Cleavage of corticosteroid-binding globulin by human leukocyte elastase results in the reduction of its hormone-binding affinity and capacity. In this communication we confirm previous observations that TBG is also cleaved by elastase and undergoes the characteristic conformational changes. In addition, contrary to a previous report, the present work demonstrates that the cleaved product has reduced T(4)-binding affinity and, as expected, increased heat stability. Additional fragmentation of the molecule results in the loss of the hormone-binding site that is in agreement with a recent in vivo observation of apparent consumption at sites of inflammation. These data suggest that TBG may play a role in the targeted delivery of thyroid hormones to tissues rich in proteinases.
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PMID:Characterization of T(4)-binding globulin cleaved by human leukocyte elastase. 1188 91