Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For naive B cells to mature in response to antigen triggering and become either plasma cells or memory B cells, a complex array of events takes place within germinal centers (GC) of secondary lymphoid organs. With the long-term objective of defining and characterizing molecules that control the generation of GC, we have subtracted RNA messages derived from highly purified B cells at the follicular mantle stage of differentiation from GC B cells. Using this approach, we have identified a novel molecule, centerin, belonging to the family of serine-protease inhibitors or serpins. Transcription of centerin is highly restricted to GC B cells and their malignant counterparts, Burkitt's lymphoma lines. The putative centerin protein shares the highest sequence identity with thyroxine-binding globulin and possesses arginine/serine at its P1/P1' active site, suggesting that it interacts with a trypsin-like protease(s). In addition, several other sequence features of centerin also indicate that it serves as a bonafide protease inhibitor. Finally, we demonstrate differentially up-regulated transcription of this novel gene by resting, naive B cells stimulated in vitro via CD40 signaling, while Staphylococcus aureus Cowan strain-mediated B cell activation fails to generate this reponse. Because CD40 signaling is required for naive B cells to enter the GC reaction and for GC B cells to survive, it is likely that centerin plays a role in the development and/or sustaining of GC.
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PMID:Identification of centerin: a novel human germinal center B cell-restricted serpin. 1106 88

Centerin [SERPINA9/GCET1 (germinal centre B-cell-expressed transcript 1)] is a serpin (serine protease inhibitor) whose expression is restricted to germinal centre B-cells and lymphoid malignancies with germinal centre B-cell maturation. Expression of centerin, together with bcl-6 and GCET2, constitutes a germinal centre B-cell signature, which is associated with a good prognosis in diffuse large B-cell lymphomas, but the molecular basis for this remains to be elucidated. We report here the cloning, expression and molecular characterization of bacterial recombinant centerin. Biophysical studies demonstrated that centerin was able to undergo the 'stressed to relaxed' conformational change which is an absolute requirement for protease inhibitory activity. Kinetic analysis showed that centerin rapidly inhibited the serine protease trypsin (k(a)=1.9x10(5) M(-1) x s(-1)) and also demonstrated measurable inhibition of thrombin (k(a)=1.17x10(3) M(-1) x s(-1)) and plasmin (k(a)=1.92x10(3) M(-1) x s(-1)). Centerin also bound DNA and unfractionated heparin, although there was no functionally significant impact on the rate of inhibition. These results suggest that centerin is likely to function in vivo in the germinal centre as an efficient inhibitor of a trypsin-like protease.
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PMID:Molecular characterization of centerin, a germinal centre cell serpin. 1744 96